Chapter 27: Toxic Effects of Calories

All biotic organisms derive energy from food to sustain life and this energy “drives” various cellular functions, including digestion, metabolism, pumping blood, and muscle contractions. Nutrients can broadly be defined as chemical substances found in food that are necessary for proper growth and development, reproduction, and repair following injury. Based on their chemical nature, nutrients can be grouped into organic (carbon-containing) and inorganic classifications. Carbohydrates, proteins, fats, and vitamins comprise the former, while minerals and water are inorganic nutrients essential for life (Stipanuk, 2006). Inorganic nutrients such as minerals can be absorbed into the body through food and are generally incorporated into the food chain through environmental sources (soil, water). Minerals comprise ~4% of the body weight in humans and in combination with water furnish a major part of the obligatory milieu necessary for cellular functioning (pH, osmolarity). Macrominerals are those whose abundance is generally 0.01% of body weight or daily required amounts exceed 100 mg per day. Calcium, phosphorous, sodium, and magnesium fall in this group. Other minerals that are not as abundant can be equally important for an organism. Trace minerals are defined as minerals whose concentration is <0.01% of total body weight. Other alternative definitions include nutrients whose requirements are below 1 ppm. Iron, zinc, copper, iodine, selenium, and molybdenum are six essential trace elements with established recommended dietary allowances. Overall, trace nutrients perform a variety of important functions, including transport of oxygen (iron as a part of hemoglobin), catalysis of biological reactions as component of enzymes (iron, zinc), and as part of other organic molecules (selenocysteine). While inorganic compounds serve important roles in physiology, the energy in food is derived from metabolism of organic substances. Organic compounds are generally synthesized by living cells from simpler molecules. For example, green plants and marine phytoplankton utilize photosynthesis to convert the very simple molecule carbon dioxide into more complex, energy-rich compounds such as carbohydrates using the energy from the sunlight. Because most bacteria and higher organisms cannot carry out photosynthesis, they derive their energy by metabolism of preformed organic molecules, such as carbohydrates. In general, bacteria utilize simpler organic molecules and animals and humans require more complex macronutrients (proteins, fats, and carbohydrates) to meet their needs.

Digestion of Foods

Common foods are a complex matrix and before the nutrients in food can be utilized they invariably need to undergo digestion. The process of digestion is a remarkable orchestration of many complex biochemical and physiological events, which occurs throughout the gastrointestinal (GI) tract, involving mechanical and chemical breakdown of food into simpler nutrients that are amenable for absorption. The upper GI tract consists of oral cavity, esophagus, and stomach. Breakdown of food begins in the mouth via the actions of enzymes in saliva. Movement of food between sections of the GI tract is restricted via sphincters or valves. In the stomach, food is acted upon by gastric juices, which are secretions from the cardiac, oxyntic, and pyloric glands in the stomach. Gastric juice contains high amounts of hydrochloric acid that is secreted from gastric parietal cells. This along with the enzymes pepsin and α-amylase acts upon proteins and carbohydrates, respectively, to generate polypeptides and simpler sugars (such as dextrins from starch). Digestion in the small intestine is aided by numerous enzymes supplied by the pancreas, liver, and gall bladder, which drain into the proximal part called the duodenum. Bile made in the liver and secreted from the gall bladder aids in the absorption of fats from the diet. Pancreatic juice contains digestive enzymes including carboxypeptidases, lipases, amylases, and nucleases. Pancreatic secretions also contain bicarbonate and divalent cations (mostly sodium and potassium) that help neutralize the acidic composition of the partially digested food from the stomach. Almost half of ingested carbohydrates and proteins, and 90% of ingested fat are digested by pancreatic enzymes. In addition to the enzymes, the small intestine itself secretes numerous enzymes including aminopeptidases, lipases, and disaccharidases.

The latter parts of the small intestine, the jejunum and ileum, are primary sites of absorption of nutrients. The surface of the small intestine is uniquely adapted to facilitate the absorption of digested nutrients. The surface area of the intestinal mucosa available for absorption is greatly increased due to a combination of folds called valvulae conniventes (folds of Kerckring) and finger-like projections (villi) that are lined with enterocytes. The luminal surface of the enterocytes is further lined by microvilli that give the mucosal surface brush-border-like appearance. The luminal and basolateral surfaces of the enterocytes are rich in transporters that mediate uptake of nutrients into the enterocytes. Absorption of nutrients into enterocytes may be accomplished by diffusion, facilitated diffusion, or active transport. Luminal digestion of complex carbohydrates involves breakdown via salivary and pancreatic amylases into dextrins that undergo further digestion to simple monosaccharides in the membrane. These are transported into the enterocytes by active transport (glucose, galactose) or via facilitated diffusion (fructose). Digestion of proteins begins in the stomach and continues in the lumen of the small intestine. The jejunum is the site of absorption of amino acids and dipeptides and tripeptides by amino acid and peptide carriers in the enterocyte brush border. Lipids in the diet such as triacylglycerols are hydrolyzed by pancreatic and intestinal lipases to free fatty acids or monoacylglycerol. Bile salts along with phospholipids facilitate the absorption of lipids by forming emulsified complexes called micelles. After uptake into the enterocyte fatty acids are reesterified and packaged into chylomicrons that exit the enterocyte into the lymphatic system. Macronutrient molecules (amino acids, sugars, and fatty acids) that end up in the circulation undergo metabolism in various tissues to be either oxidized to extract energy or stored for future utilization.

Integrated Fuel Metabolism

The requirement for energy to fuel cellular functions in all organisms is continuous. However, food consumption is intermittent. Hence, most organisms have developed processes to store energy from a meal to be utilized until the next meal. Energy in the body is derived from three main nutrient classes: carbohydrates, protein, and fat, which in turn are made up of sugars, amino acids, and free fatty acids, respectively. The principal circulating fuels in the body, glucose and free fatty acids, are stored as glycogen and triglycerides, respectively. Highest concentrations of glycogen are present in the liver and skeletal muscle, which is a macromolecule consisting of branching chains of glucose held together by α-1,4 and 1,6 linkages. Triglycerides are stored in adipose depots in specialized cells (adipocytes) within large lipid droplets. While total body protein constitutes a large percentage of the energy, unlike fats and carbohydrate, protein is not normally utilized as storage form of energy. Proteins are critical in maintaining structure and function and are catabolized for energy only as a last-ditch effort, under extreme conditions. The energetic value of macromolecules per gram of tissue is influenced based on their hydration. While the theoretical energy content of glycogen is ~4 cal/g, due to its highly hydrophilic nature, each gram of glycogen is associated with two to three times its weight of water. Hence, in reality glycogen provides approximately 1 kcal/g of actual energy. This makes storage of energy predominantly in the form of glycogen quite inefficient. In contrast, because triglycerides are stored in a mostly nonaqueous milieu, fat tissue is energy dense, yielding close to the theoretical 9.4 cal/g of triglyceride. Hence, most animals have developed systems to convert glucose into lipids (lipogenesis) and adipose depots to store de novo synthesized lipids.

The interconversion of fuel sources and release in the time of need is designed to address three priorities of fuel utilization (Shulman et al., 2003). Maintaining a stable supply of substrate for utilization by the brain is the first priority. Because the brain has little to no stored energy in the form of glycogen or triglycerides, it exclusively depends on the liver for maintaining a continuous supply of glucose. Blood glucose concentrations are maintained within a narrow range (55–140 mg/dL) via a number of interrelated mechanisms that are highly conserved. Unlike the brain, the heart and to some degree the liver and skeletal muscles derive most of their energy needs through the oxidation of fatty acids. Maintenance of protein reserves and replenishment of proteins (enzymes, cytoskeletal proteins, contractile proteins) following feeding is the next important function of fuel metabolism. Finally, conversion of existing nutrients into their storage forms (glycogen and triglycerides) is carried via anabolic biological pathways (glycogenesis and lipogenesis).

Hormonal messages generated by the endocrine cells of the pancreas, adipose tissue (adipokines), and GI tract (gut neuropeptides) are critical to orchestrating the multiple processes associated with fuel flux and metabolism. Insulin is the principal hormone required to manage nutrient fuels in both fed and fasted states. The presence and subsequent absorption of food in the GI tract and rise in blood glucose stimulates insulin secretion from the pancreas. Through its actions on various signaling pathways, insulin promotes glucose uptake in peripheral tissues, glycogen synthesis in the liver and muscle, lipid synthesis in adipocytes, and amino acid and protein synthesis in most cells. Insulin also acts to restrain catabolic processes such as lipolysis, gluconeogenesis, and protein degradation, which classically occur under states of low insulin (such as fasting). Following the immediate disposal of absorbed nutrients, the body enters a postabsorptive (early fasting) state, during which energy can no longer be derived from glucose directly from the meal (Ruderman et al., 2005). In this state, serum levels of insulin start to decrease, and the liver begins catabolic processes, first glycogenolysis and then de novo synthesis of glucose (from gluconeogenic precursors, lactate and fatty acids, and glycerol). The substrates for gluconeogenesis arrive from anaerobic metabolism of glucose in red blood cells or metabolism of triglycerides and fatty acids (in adipose tissues). If food remains unavailable for a further protracted period of time, glycogen levels are almost completely depleted in both the muscle and liver and amino acids (released from breakdown of proteins) become the primary source for glucose production. A rise in glucagon and glucocorticoids (such as cortisol) also characterizes this state. These hormones promote lipolysis and breakdown of glycogen.

Set-Point Theory and Neural Control of Energy Balance

A number of redundant feedback mechanisms operate to maintain the homeostasis of energy in living systems. These mechanisms eventually regulate the balance between food intake and energy expenditure to maintain fuel reserves at preset levels. Under steady-state conditions, energy consumed is normally metabolized and utilized to maintain basic metabolic rate and thermogenesis, and carry out cellular processes, organ-specific functions, and movement (muscle contractions). Excess fuels are converted to triglycerides and stored in adipose tissues. Because adipose tissue is the major depot of preserving energy, signals derived from the periphery signal to regions in the brain that coordinate energy balance. When total energy consumed equals the total energy required to meet basal metabolic needs, growth, thermogenesis, and physical activity, the individual is in energy balance, and maintaining this balance will result in relatively stable weight and healthy body composition. When energy intake exceeds the actual energy expenditure, weight gain ensues and body composition can become problematic. The existence of a precise energy balance system is illustrated by considering normal variations in weight among groups of individuals over time. Over the course of a year, the average adult male consumes about one million cal, yet body weight of most weight-stable individuals does not fluctuate more than 1 lb. Even a small (~5%) error in matching intake and expenditure would result in a net change of approximately 6 kg of body weight. Therefore, it is obvious that mechanisms operating within the body can regulate energy balance with exquisite precision.

One theory called the “set-point” hypothesis proposes that food intake and energy expenditure are coordinately regulated by defined regions in the central nervous system that signal to maintain a relatively constant level of energy reserve and body weight (Keesey and Hirvonen, 1997). It is posited that the status of energy stores is sensed by the central nervous system and changes in the afferent signal result in adjustments in food intake and/or energy expenditure. Implicitly, the model requires the existence of four major components of an energy homeostasis system: afferent signals relaying the levels of energy stores, efferent processes regulating energy storage and expenditure, efferent mechanisms controlling ingestive behavior, and integrative centers in the brain to coordinate these processes. Studies have shown that the hypothalamus plays a central role in the control of energy balance, especially food intake. The hormone leptin, secreted in proportion to body fat stores from the adipose tissue, was the first signal to be identified to be a homeostatic regulator of energy balance. Leptin acts on metabolic-sensing neurons in the brain receptor-mediated actions, regulating signaling pathways that in effect decrease food intake (Friedman and Leibel, 1992). Leptin also has potent neurotrophic actions in the brain.

Two populations of neurons are seat of appetite control machinery in the brain, both of which are sensitive to leptin's actions (among other neuropeptides), one expressing orexigenic peptides neuropeptide-Y (NPY) and agouti-related peptide (AGRP) and the other expressing anorexigenic peptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). These are located in the arcuate nucleus of the hypothalamus. Downstream projections from these neurons interact with the melanocortin receptor neurons and the neurons in the paraventricular nucleus of the hypothalamus. In addition to the hypothalamic control of appetite per se, reward and hedonic processes of “liking” and “wanting” food occur in the ventral striatum of the midbrain in conjunction with the mesolimbic dopamine system. In addition, the corticolimbic system of reward is controlled by areas in the prefrontal cortex, which integrates sensory, emotional, and cognitive information to coordinate behavioral responses (Lenard and Berthoud, 2008). Hence, the homeostatic control of energy balance fits into the larger decision scheme of choice behavior via a complex neural system.

Assessing Caloric Intake

In animal studies, caloric intake can be quantitatively monitored by measuring the amount of food consumed by animals in metabolic cages. Caloric intake can be derived by multiplying the quantity (g per day) of diets consumed with the caloric density of the diet. Knowledge of caloric intake is important in many experimental designs where pair-feeding a parallel cohort of animals is necessary. In clinical studies, assessing caloric intake can be performed in a number of ways, each with its strengths and limitations. A prospective method to collect information about current intake is maintenance of food records. These are usually carried out for a specific duration of time (three to seven days, generally including both week and weekend days) during which a written record of all food and beverages consumed is maintained. Quantification is performed by estimation of weights or actual weighing of foodstuff, and hence food records provide both qualitative and quantitative data. Advantages include high reliability as records do not rely on memory and can provide detailed records of diet and nutrient intake. However, weighed records are both labor and cost intensive and place higher burden on participants. Habitual eating habits can be influenced by the process of recording and the reliability of the method decreases over long periods of data collection. Collected data are analyzed using a nutritional database such as the Nutrition Data System for Research (University of Minnesota). Several methods of dietary assessment rely on retrospective collection of food intake. The diet history and food recall are commonly used methods in clinical research, where a trained individual obtains details of participant's habitual dietary intake in-person or over the phone. Details may include portion sizes, cooking methods, and patterns of eating. The techniques allow a large amount of descriptive data to be collected. Most usually, the interviewer incorporates a 24-hour or three-day window in which detailed recall is obtained. Burden on the participant is low; however, the technique involves considerable training and time on the part of the researcher. Recall interviews can sometimes be time-consuming and several recalls may be necessary to obtain useful information. Again, analysis of the collected data using a nutritional database is necessary to get quantitative measures of nutrient and caloric intakes. Food frequency questionnaires (FFQ) are tools that can be self-administered or provided in an interview setting to participants. FFQ collect information about consumption of each food from a list of foods over a specified period of time (eg last six months). They are devoid of specific data regarding the portion sizes and cooking method and are not an appropriate method for quantifying intakes. However, FFQ are useful in gathering information on long-term food patterns, in a low-burden and inexpensive method. Both of these methods are merely estimations and can have significant errors.

Assessing Caloric Content of Foods

Accurate assessment of the caloric value of foods is essential for effective nutritional management in clinical and public policy arenas. Classical investigations by Professor Atwater and his colleagues providing the general calorie factors of 4, 9, and 4 for the major sources of energy—carbohydrate, fat, and protein—have been widely used. Both fats and carbohydrates can be completely oxidized to water and carbon dioxide, while protein is incompletely oxidized and partly excreted from the body as urea. The heat released by combustion of a food in a bomb calorimeter is a measure of its gross energy. However, not all the ingested energy will be available for metabolism and digestible energy refers to the fraction following losses of energy as fecal energy and gases from microbial fermentation. The truly metabolizable energy can be derived by accounting for lost energy in urine (mainly from nitrogen) and on the body surface. Analytical methods to determine the macronutrients in food, protein, fat, and carbohydrates in addition to alcohol and other organic acids, have been described widely (Tontisirin et al., 2003). Protein content is mainly determined via estimating nitrogen content by either the Kjeldahl method or hydrolysis of proteins into amino acids and then measuring concentrations using gas or high-pressure liquid chromatography. Fat content can be assessed by measuring the sum of methanol–chloroform extractable total fatty acids that can be expressed as triglyceride equivalents. Total fat can also be assessed by gravimetric methods. Carbohydrate content is generally measured by difference as the remaining energy after accounting for protein, fat, alcohol, and ash. This measure of carbohydrate included energy from fiber as well as some components that may strictly not be carbohydrates (organic acids).

Assessing Energy Expenditure

The process of oxidative phosphorylation couples the oxidation of nutrients with the synthesis of high-energy molecules (viz, adenosine triphosphate [ATP]), the main energy currency of the cell. The energy stored with these molecules is utilized to power all the biochemical processes in cells, which encompass metabolism, growth, and cell division. The total energy expenditure (TEE) or metabolic cost for an average adult ranges from 1500 to 3000 kcal per day. A calorie is defined as a unit of energy that is required to raise the temperature of 1 g of water by 1°C. TEE is primarily composed of three components: (1) basal energy expenditure, (2) thermic effect of food (TEF), (3) energy expenditure associated with physical activity (EEPA). While most of the variance in daily TEE is accounted for by the three aforementioned components, a small fraction of energy expenditure is accounted for by adaptive thermogenesis (energetic cost of cold adaptation). Basal energy expenditure, also called as resting energy expenditure (REE), is the energy expended when the individual is lying down and at complete rest, generally after sleep in the postabsorptive state. REE accounts for almost 60% of TEE (Gropper et al., 2005). A close surrogate of REE is the resting metabolic rate (RMR). TEF, which accounts for 10% to 15% of TEE, is the energy expenditure associated with the digestion, absorption, and storage of food. EEPA consists of (1) expenditure related to planned exercise and (2) nonexercise activity thermogenesis (NEAT). The former refers to purposeful physical activity, which varies in most individuals and is negligible in individuals who do not participate in exercise. However, even in individuals who do undertake regular exercise, NEAT contributes the greater proportion to EEPA. NEAT includes all energy expenditure from occupational and leisure activities (sitting, climbing stairs, walking, fidgeting, etc).

Components of energy expenditure can be measured using either (1) direct or (2) indirect calorimetry. The basic principle in direct calorimetry is to measure the actual heat produced by the organism in a highly controlled environment as an estimate of energy expenditure. In large organisms (such as human subjects) this is generally impractical due to the large inherent capacity to store heat. Further, due to limitations in the design, complexity, and cost of carrying out direct calorimetry, it is seldom utilized. The most commonly used methods to estimate energy expenditure, therefore, involve indirect calorimetry. Since most aerobic organisms derive energy from oxidation reactions, consumption of oxygen can serve as reliable surrogate for heat production. Using experimentally derived estimates for energy yields per mole of oxygen for the main fuel substrates, heat production can be calculated based on the quantity of oxygen consumed. Indirect calorimetry can be coupled with specific tracer techniques to examine the utilization and metabolism of specific substrates in both whole body and tissue-specific compartments. The ratio of carbon dioxide expired and oxygen consumed is called the respiratory quotient (RQ). RQ estimates can be useful in understanding both energy expenditure and overall substrate oxidation. An RQ value of 1.0 suggests that carbohydrate is being oxidized, because under these conditions the amount of oxygen required for oxidation of glucose is equal to the amount of carbon dioxide produced. The representative average RQ values for carbohydrate, fat, and protein are 1.0, 0.7, and 0.8, respectively. Indirect calorimetry can be assessed in animals by placing them in closed chambers in which airflow is controlled at specified flow rates. Oxygen and carbon dioxide concentrations are assessed using gas analyzers to calculate RQ values. Specialized chambers that are commercially available integrate measurement of body weights, food and water intake, activity, and oxygen consumption in a single chamber. In human subjects, the same principle is utilized to assess oxygen consumption in a variety of designs. A simple metabolic cart can be utilized to assess basal metabolic rate (BMR) in individuals over a short 30-minute period while the individual is in the supine position, but not asleep. Estimates of 24-hour RMR can be calculated by extrapolation. Metabolic carts can be adapted to estimate energy expenditure during physical activity such as treadmill running to estimate maximal oxygen consumption (VO₂ max). However, these measurements only estimate the REE component of TEE. Room calorimeters allow estimating the true TEE by measuring oxygen consumption during all aspects of free living, including postmeal thermic expenditure and during physical activity. These studies require the participant to be isolated in a room calorimeter and are expensive to undertake and maintain. Another method to estimate TEE in free-living subjects utilizes measurement of stable isotopes ²H₂ (deuterium) and ¹⁸O. In this technique referred to as “doubly labeled water,” a stable isotope of water is given to individuals (H₂¹⁸O and ²H₂O) and the disappearance of the labeled tracer in blood and urine is assessed over three- to six-week time period. The labeled water incorporates into the body water pool and estimates either the water turnover alone (²H label) or the turnover of water and production of CO₂ (¹⁸O label). The difference between the two rates of loss of the two labels corresponds to the rate of production of CO₂. The amount of oxygen consumed is indirectly calculated via food records (food quotient) over the assessment period. RQ and energy expenditure can then be calculated using the volumes of oxygen and carbon dioxide. RMR estimates can also be calculated nonexperimentally based on derived equations. Equations such as the Harris–Benedict equation and the Mifflin and St. Jeor equation utilize the person's body weight, body surface area, age, gender, and height.

Assessing Body Composition

Body composition assessments are aimed at describing the overall mass of an individual organism in terms of its molecular or nutrient components: water, fat mass, lean mass, protein, and minerals. In a simple two-compartment model of body composition assessment, total body mass is divided into fat mass (essential and nonessential fat) and fat-free mass (including lean mass and water). Lean mass in this scenario includes protein, carbohydrate, and minerals. A number of techniques have been developed to indirectly assess either specific components or all measures of body composition.

Anthropometric Analysis

Body mass is an obvious, but poor surrogate to relative fat mass. While individuals with greater body weight (mass) per height tend to have greater fat mass, total body weight may also be determined by increased muscle mass. Taller people on average have greater weight and weight and/or body composition also changes more dynamically with age. Hence, the simplest indirect measure of body fatness is the relative proportion of weight to height, more commonly referred to as body mass index (BMI). BMI is derived by ratio of mass (in kilograms) and square of height (in meters). The advantage of BMI is that it is easy to compute and large worldwide reference datasets exist. BMI, however, is only an estimate and because BMI does not always reflect fat mass, care must be taken when using BMI as a fat index. Other anthropometric estimates of body composition include measurement of skin folds and circumference at various sites (abdomen, waist, hip). The general assumption is that total body fat is proportional to the fat deposited beneath the skin. Measurements can be analyzed by utilizing several regression models that predict percent body fat. Five commonly employed sites include triceps, subscapula, suprailiac, abdomen, and thigh. While the technique is inexpensive to perform, sites chosen for analysis and skill of the anthropometrist influence the accuracy of the results.

Hydrodensitometry

The principle used to calculate body density using hydrostatic weighing has been known since antiquity when the Greek mathematician Archimedes showed that the density of an object is the ratio of its weight in air to its loss of weight in water. Using the density of the whole body and correcting for residual air in the lungs and GI tract, the relative body fat can be estimated using derived equations by Siri or Brozek. This procedure is also known as underwater weighing.

Air Displacement Plesmography

This procedure employs the same principles as underwater weighing described above, except rather than the body displacing water, it displaces air. This allows the body volume to be calculated and then body fat can be calculated. This is probably the most accurate, precise, and cost-effective measure of total body fat, and is employed widely in clinical research in the United States.

Absorptiometry

This is one of the most widely used tools in assessing body composition. In this technique imaging is performed throughout the entire body by a photon beam. Most investigations using this technique use either a dual-photon source (gadolinium) or x-ray at two different energy levels (dual-energy x-ray absorptiometry [DXA]). Hence, this allows imaging of both soft tissues and bone. The attenuation of the x-ray signal received on the detector is proportional to the density of the tissue. Percentage of body fat, lean tissue, and bone mineral density can be computed for the whole body or specific sites based on the analysis of images.

Computerized Tomography

While utilizing similar principles of differential x-ray attenuation through body, computerized tomography is used to produce three-dimensional “slices” or cross-sectional images of the subject. This is made possible by positioning the x-ray source and detectors on opposite poles of a circular tube within which the subject is imaged. The ability to generate 3D images allows regional localization of adipose tissues, muscles, and organs (liver). Using the image data, percent body fat and lean mass can be calculated.

Nuclear Magnetic Resonance (NMR)

NMR works by interpreting radio-frequency signals of excited nuclei in an external magnetic field. The physical characteristics of the hydrogen atom differ when the hydrogen is located on protein, fat, or water and this can be detected and quantitated to determine body composition. Magnetic resonance imaging (MRI) is an extremely powerful imaging technique with high-resolution capacity and employed widely as a clinical diagnostic tool. Images acquired are three-dimensional allowing detailed analysis of body composition and regional fat and lean mass distribution with depots and ectopic deposition within tissues. While MRI has several advantages in terms of assessing the distribution of body fat, its expense relative to NMR makes it less used, and other considerations such as the requirement for the participant to lay still during the scanning period and the extreme noise make MRI less applicable than NMR for children.

Electrical Impedance

Bioelectrical impedance analysis (BIA) and total body electrical conductivity (TOBEC) measure total body composition based on measuring electrical impedance (the inverse of conductance) of an electric current passed through the body. The conductance of a weak painless current through the body (which serves as an electrolytic medium) is utilized to infer lean body mass and fat mass. Lean mass has more water and greater conductivity than fat mass and predictive equations are employed to derive fat and lean body mass.

Total Body Water

Body fat and lean mass can be calculated by estimating total body water using stable isotopes. Dilution of water containing specific concentrations of labeled isotope (either deuterium or ¹⁸O) is usually assessed. Concentrations of isotopes are measured in blood or urine over a timecourse following a two- to six-hour equilibration period. Since body water occupies 73.2% of lean mass, fat-free mass can be computed based on total body water. Using a three-compartment model fat mass can be calculated. The method is significantly influenced by hydration status and assumptions are confounded by water present in fat tissue. While the cost of chemicals and collection of samples is not high, analysis of stable isotopes can be expensive.

Assessing Physical Activity

Accurate quantification of physical activity in free-living subjects is challenging. Methods utilizing self-reported diaries and questionnaires tend to overestimate physical activity. Devices such as accelerometers and pedometers can be utilized to empirically estimate activity. Accelerometers are versatile and cost-effective and can measure activity with little subject burden. Existing accelerometers come in varying degrees of sophistication from simple pedometers that count steps to models that can assess motion in three dimensions. An important challenge in utilizing accelerometers is to convert the count data into energy expenditure, which is done using different regression models.

Obesity Risk: Genes, Epigenetics, and Fetal Environment

Access to plentiful food has been unpredictable throughout most of human (and animal) developmental history, marked by periods of feast or famine. In evolutionary terms, fitness and survival of an individual were likely to be closely related to the ability to maximally seek, acquire, consume, and store energy (as fat) when food was available, and to select for mechanisms that reduce energy expenditure during times when food is scarce. Thus, selection favored so-called thrifty genes that orchestrate anabolic processes over energy-consuming ones and provide selective advantage to those who possessed them during periods of food deprivation (Neel, 1962). However, the advent of agrarian lifestyle and recent industrialization has meant that much of the developed and emerging world now has a drastically altered environment. Food is generally available for most people and our lifestyles require less physical activity and exertion. Hence, the genetic legacy of once beneficial thrifty genes placed in an environment of caloric abundance acts as a powerful engine for weight gain, obesity, and its associated metabolic dysfunction. Recently questions have been raised whether the selection of thrifty genes occurred because of a true advantage contributing to survival. Speakman has proposed that natural variation and random mutation (genetic drift) in genes controlling hypothalamic energy balance set-points occurred in human evolution as human beings developed fire and social behaviors, and were released from risk of predation. This theory referred to as the “drifty gene” hypothesis better explains why even in societies where obesity is high, not everyone becomes obese (Speakman, 2008). Obesity is a highly heritable trait and studies comparing monozygotic with dizygotic twins indicate that 40% to 75% of the interindividual difference in trait is accounted for by genetic variability. Several genes whose disruption causes severe monogenic forms of familial obesity have been described. Remarkably, most of these genes impair central control of food intake. However, the genetic basis of nonsyndromic (common) obesity has remained elusive.

Recent genome-wide association studies (GWAS) have been highly effective in identifying common genetic variants that impact adiposity and other aspects of the metabolic syndrome (MetS). To date 50 such obesity-associated loci have been identified with high confidence (O'Rahilly and Farooqi, 2008). Of these the FTO (fat mass and obesity associated) is unequivocally associated with increased risk of obesity. Individuals who are homozygous for the high-risk (AA) allele weigh on average 3 kg more than individuals who do not carry any risk allele. New meta-analysis of GWAS studies including ~250,000 subjects has revealed 18 novel loci associated with BMI. Overall, the presently identified loci in combination still explain only a small proportion of obesity. Epigenetic regulation of gene expression is another area that might explain the underlying differences in susceptibility to obesity.

Epigenetics is loosely defined as heritable changes in modifications to the DNA that do not alter the DNA sequence. DNA methylation and covalent modification of histone tails are examples of epigenetic regulation. It is clear that epigenetic mechanisms are involved in basic cell functions including proliferation, differentiation, and growth. Because DNA methylation patterns can also be affected by environmental influences (in utero environment, exposure to xenobiotics, stress), it is plausible that interaction of certain risk alleles and epigenetic mechanisms are responsible for susceptibility to obesity.

The incidence of obesity continues to rise and prevalence even among infants is rapidly rising. As for many chronic diseases, it is now widely accepted that increased susceptibility to obesity can be programmed in utero and early postnatal life. This hypothesis referred to as the “fetal origin of adult disease” is derived from the findings by Professor David Barker and colleagues at the University of Southampton, who discovered an inverse relationship between birth weight and risk of mortality due to coronary heart disease (Barker et al., 1989). Over the last two decades, epidemiological studies have extended the initial associations between birth weight and later cardiovascular disease to include associations between early growth patterns and risk for hypertension, insulin resistance, type 2 diabetes, and obesity in later life. Experimentally manipulating birth weights in a variety of animal models (rats, mice, sheep, pigs) also recapitulates the developmental programming phenotype (McMillen and Robenson, 2005). Another important influence on risk of obesity in later life is maternal body composition (fat mass) at conception and gestational weight gain. Studies in women and experimental models clearly indicate that maternal diet and body composition during pregnancy influence aspects of metabolism and appetite regulation in the offspring (Shankar et al., 2008). The mechanisms of such programming presumably involve epigenetic mechanisms.

Many of the adaptive, physiological responses to a positive energy balance produced as a result of overeating and inadequate physical activity result in toxicity over the long term. Short-term coordinated changes in metabolic pathways in white adipose tissue in response to overfeeding result in excess energy storage in the form of triglycerides and increased size of preexisting adipocytes (hypertrophy), and this also leads to formation of new adipocytes through hyperplasia (Virtue and Vidal-Puig, 2010). However, management of excess ingested energy over the long term can be complex. Under such conditions, the efficiency of energy storage in adipose tissue is decreased and the body has to resort to several different options to store energy in addition to fat, such as in ectopic sites, which may in fact be detrimental. As plasma concentrations of nonesterified fatty acids (NEFA) increase as a result of ingestion of high-fat diets and as a result of hydrolysis of triglycerides in the fat, triglycerides begin to accumulate in nonadipose tissues such as liver, skeletal muscle, and the pancreas as lipid droplets. The presence of excess NEFA and lipid metabolites in these tissues results in direct and indirect toxic actions leading to insulin resistance, inflammation, and tissue damage.

In addition, adipose tissue from obese individuals releases chemokines and cytokines, the so-called adipokines, which contribute to a state of “metabolic inflammation” (Gustafson, 2010; Dulloo et al., 2010). Fat is also an endocrine organ and the pattern of adipokines produced by adipose tissue in obesity differs substantially from that seen in lean individuals (Cornier et al., 2008).

NEFA and the other factors released from adipose tissue contribute to the development of the Metabolic Syndrome “MetS” in some overweight and obese individuals. This is a cluster of components including insulin resistance, disruptions in lipid homeostasis (dyslipidemia), and elevated blood pressure that substantially increase the risk for development of cardiovascular disease and type 2 diabetes. MetS is also associated with other comorbidities including nonalcoholic fatty liver disease (NAFLD) and reproductive dysfunction and elevated serum insulin in response to insulin resistance contributes to increased cancer risk associated with obesity. As a consequence, overall mortality is increased and life span is shortened with increasing caloric intake, body weight, and adiposity, whereas caloric restriction (CR), at least in animal models, has been shown to substantially increase life span.

Adaptation of Liver and Adipose Tissue to Excess Calories

Triglycerides and glycogen are used by the body to store excess caloric energy. This is a homeostatic mechanism that maintains energy sources such as blood glucose levels between meals. Dietary fats are transported in blood from the gut to the liver and adipose tissue by lipoprotein particles called chylomicrons. In both tissues, local hydrolysis of triglycerides in the capillary bed by the enzyme lipoprotein lipase results in the release of free fatty acids that are subsequently taken up into hepatocytes and adipocytes via fatty acid transport proteins (FATPs) and the scavenger receptor CD36. As they enter the cell, free fatty acids that are toxic are immediately conjugated with acetyl CoA and are bound to intracellular fatty acid–binding proteins before reesterification with glycerol to form triglyceride lipid droplets in the cytosol. Such droplets are highly dynamic and are coated with PAT proteins (named after perilipin, adipophilin, and the tail-interacting protein). Adipophilin and perilipin have important roles in droplet stabilization and regulation of triglyceride turnover. The hepatocyte cytosol contains many small droplets that vary in size depending on the length of time after a meal, dietary fat to carbohydrate ratio, type of dietary fat, and overall caloric intake relative to metabolic requirements. The small hepatic lipid droplets function as a temporary energy storage site, whereas in adipocytes the small lipid droplets fuse to form a single large storage droplet and can serve as a longer-term storage site. In the hours after a meal, triglycerides from the hepatic droplets are incorporated into the lipoprotein VLDL, which is secreted into the plasma and which transports hepatic triglycerides to the adipose tissue for storage. Removal of triglycerides from VLDL by lipoprotein lipase in adipose and other peripheral tissues results in generation of the more dense lipoprotein LDL, which is subsequently recycled by the liver as the result of endocytosis on binding to the LDL receptor (Olson, 1998).

Although obesity is often associated with overconsumption of high-fat diets, it can develop from excessive caloric intake of any food energy source, including carbohydrates and proteins. Although overall consumption of dietary fat has declined in the United States over the past two decades, the proportion of obesity has increased to epidemic levels. In part this is due to excessive intake of simple carbohydrates that have increased as dietary fat consumption has decreased. Dietary carbohydrates are converted to monosaccharides, mainly glucose and fructose, which are further metabolized in the liver and peripheral tissues. Excess glucose can be stored in the liver in the form of the glucose polymer glycogen that accumulates as cytosolic granules and can make up as much as 7% of liver weight. However, the majority of excess hepatic glucose is metabolized via glycolysis and the citric acid cycle to acetyl CoA and is shunted into de novo fatty acid and triglyceride synthesis.

Recent DNA microarray analysis of gene expression in human adipose tissue biopsies suggests that coordinated upregulation of lipogenesis occurs in fat rapidly and directly as a result of increased caloric intake independent of changes in body weight (Franck et al., 2011). Evidence for increases in adipose tissue glucose transport, and fatty acid and triglyceride biosynthesis has also been obtained from microarray analysis of fat from rats overfed a mixture of simple carbohydrates and fat (Shankar et al., 2010). The increase in triglyceride synthesis in both liver and fat after consumption of excess calories appears to be driven by activation of two important diet-sensitive transcription factors: sterol regulatory element-binding protein (SREBP-1c) and carbohydrate response element-binding protein (ChREBP) (Postic and Girard, 2008), and this process in fat ultimately drives adipose tissue hypertrophy. In addition to fat cells getting larger, excess calories also trigger proliferation and differentiation of preadipocytes in adipose tissue depots into new adipocytes, a process known as hyperplasia. However, the degree to which hyperplasia contributes to the ability of fat stores to expand in response to the need to store excess energy relative to hypertrophy remains unclear. What is clear is that in some individuals, there is a limit to which adipose tissue can expand safely without damage to adipocytes and that when this limit is reached toxicity results.

Recent studies have shown that when fat mass increases excessively, adipose tissue undergoes extensive structural remodeling. An extracellular matrix (ECM) with high concentrations of collagen fibrils and fibronectin appears to be essential for maintenance of the structural integrity of adipocytes and for preadipocyte differentiation (Divoux and Clement, 2011). However, at the point when adipocytes reach a certain size limit within a particular fat pad, hypoxia appears to develop possibly as a result of restricted blood flow. This triggers expression of the transcription factor hypoxia-inducible factor 1 (HIF-1α). Evidence from HIF-1α transgenic and knockout mice suggests that HIF-1α regulates inappropriate ECM remodeling and development of fibrosis in adipose tissue in response to hypoxia and obesity (Halberg et al., 2009). Fibrosis has been reported to be increased in subcutaneous adipose tissue from obese subjects compared with lean subjects both by staining of collagen fibrils and by analysis of col6a3 gene expression and the percentage of fibrosis in white adipose tissue has been shown to correlate with inflammation in morbidly obese subjects (Divoux and Clement, 2011). Further evidence linking adipose tissue ECM with limitations in the ability of fat pads to expand to store excess caloric energy and for limited adipocyte hypertrophy to precede the development of obesity-linked pathologies such as inflammation and MetS comes from studies with mice in which genes involved in ECM formation have been knocked out. The protein SPARC is required for appropriate collagen synthesis during ECM remodeling. Both SPARC−/− mice and obesity-prone ob/ob mice where the collagen VI gene has been deleted display increased adipocyte and fat pad size, loose ECM structure, and reduced inflammation and metabolic disturbances after high-fat feeding. It is thought that complex interactions between enlarging adipocytes and a fibrotic ECM trigger activation of MAP kinase pathways such as c-Jun N-terminal kinase (JNK) resulting in development of adipocyte insulin resistance, apoptosis, and necrosis, which in turn results in activation of resident macrophages in the fat and an inflammatory response (Divoux and Clement, 2011) (see Fig. 27-1).

Ectopic Fat Deposition

In general, there is a positive correlation between increased BMI and inappropriate accumulation of lipids in tissues other than fat. The major sites for this ectopic fat deposition are liver and skeletal muscle. However, lipid accumulation in other tissues such as small intestine, pancreas, and uterus has also been reported to be associated with chronic consumption of high-fat diets and development of obesity. Correlation between central (visceral) adiposity, waist circumference, and ectopic fat deposition is better than for BMI and is also highly correlated with progressive insulin resistance. However, the relationship between adiposity, ectopic fat accumulation in liver and muscle, and insulin resistance is highly complex and is strongly affected by diet composition, exercise, and race (Lara-Castro and Garvey, 2008).

In the liver, intrahepatocellular lipid accumulation, also known as fatty liver, or steatosis, is defined as an increase in hepatic lipid content above 5% by weight and is characterized in paraffin-stained sections by the appearance of multiple round empty vacuoles in hepatocytes displacing the nucleus to the periphery of the cell. To confirm that steatosis is actually present, additional staining of frozen sections for triglycerides using stains such as Oil Red O is required. Abnormal lipid accumulation in the liver in the absence of heavy alcohol usage is referred to as non-alcoholic fatty liver disease (NAFLD) and is associated with a wide spectrum of hepatic dysfunction. The incidence of NAFLD in the general population including children has increased in line with increasing incidence of obesity and is observed in >50% of adult obese patients (Browning et al., 2004). Simple steatosis is generally reversible with weight loss and/or lifestyle modification (diet and exercise). However, a small proportion of patients progress to more severe liver pathologies (see below). Hepatic lipid accumulation can occur as the result of one or more of the following: (1) increased fatty acid supply to the liver and increased fatty acid transporter expression; (2) increased de novo fatty acid and triglyceride synthesis; (3) decreased fatty acid oxidation; and (4) decreased synthesis and/or secretion of VLDL. Which of these processes predominates depends on the degree of obesity, total caloric intake, and diet composition. As the capacity of adipose tissue to expand is compromised with increasing BMI and insulin resistance develops in adipocytes, there is an increase in plasma non-esterified free fatty acids (NEFA) as the result of increased hydrolysis of triglycerides in fat by two enzymes—hormone-sensitive lipase and adipose triglyceride lipase. Increased hepatic exposure to NEFA derived from adipose tissue or from dietary fats has been reported to increase fatty acid transporter expression in hepatocytes (Baumgardner et al., 2008a; Marecki et al., 2011). In contrast, excess calories in the form of simple carbohydrates results in increased de novo hepatic fatty acid synthesis (Shankar et al., 2010). The type of dietary fat can also influence the development of steatosis. For example, it has been shown that saturated and polyunsaturated fatty acids can interfere with VLDL secretion relative to monounsaturated fatty acids via different mechanisms; whereas polyunsaturated fatty acids provoke oxidative stress and degradation of ApoB100 in hepatocytes, saturated fatty acids appear to block VLDL secretion via stimulation of an unfolded protein response and endoplasmic reticulum (ER) stress (Pan et al., 2004; Caviglia et al., 2011). In addition to increased NEFA, adipose tissue inflammation also appears to significantly contribute to development of NAFLD. Positive correlations have been reported between expression of macrophage markers in adipose tissue and liver fat content independent of total fat mass (Lara-Castro and Garvey, 2008).

Moreover, disrupted adipokine secretion also plays a role. The adipokine adiponectin acts on the liver to inhibit fatty acid synthesis and increase fatty acid degradation through activation of the AMP kinase cascade, downstream inhibition of SREBP-1c, and activation of the transcription factor peroxisome proliferator–activated receptor (PPAR)α. Reduced serum concentrations of adipokine adiponectin that accompany development of obesity will result in increased hepatic fatty acid synthesis and reduced fatty acid degradation and thus contribute to development of steatosis (Shankar et al., 2010).

The other major site of ectopic fat deposition in obesity is skeletal muscle in the form of intramyocellular lipid (IMCL). Skeletal muscle contains an intracellular pool of stored triglyceride that exchanges with circulating free fatty acids. Although older methods such as biochemical extraction and computer tomography scans could quantitate muscle tissue triglycerides, more recent approaches such as Oil Red O staining of frozen sections and proton NMR spectroscopy are capable of quantifying IMCL distinct from extramyocellular fat in muscle tissue. Using these methods, IMCL has been shown to positively correlate with visceral adiposity. Various mechanisms have been proposed to underlie accumulation of IMCL in obesity. In adults it has been suggested that changes in intracellular distribution of the fatty acid transporter CD36 from soluble to membrane-associated pools are responsible for increased import of NEFA and triglyceride accumulation (Nickerson et al., 2007). In contrast, data from a pediatric model of obesity demonstrated increased CD36 mRNA and protein expression in skeletal muscle associated with appearance of IMCL (Marecki et al., 2011).

Metabolic Syndrome

The development of central obesity as a result of overnutrition and a sedentary lifestyle leads to a clustering of metabolic and physiological components in some individuals that is associated with a doubling of cardiovascular disease risk and a fivefold increase in incidence of type 2 diabetes originally described as “syndrome X” by Reaven (1988) or “insulin resistance syndrome” and more recently as MetS (Cornier et al., 2008). Although the definition of MetS differs by health agency, all tend to agree that the core components include central obesity (waist circumference), insulin resistance (increased fasting glucose above 100 mg/dL and increased fasting insulin, as a result of impaired glucose uptake into skeletal muscle/fat and increased glucose output by the liver, resulting from end-organ insensitivity to insulin), dyslipidemia (decreased serum HDL below 40 mg/dL in men and 50 mg/dL in women, and increased serum triglycerides above 150 mg/dL), and hypertension (blood pressure higher than 130/85). The worldwide incidence of MetS is increasing rapidly with the obesity epidemic and is influenced by sex, age, and ethnicity. In the United States, prevalence of MetS is around 30% with higher rates in Mexican Americans than in white non-Hispanics and African Americans and increases with age into the sixth decade. Although there are no established criteria for MetS in children and adolescents and prevalence values depend on age, population studied, and definition, among adolescents, overall incidence has been estimated to be 4.2% rising to 28.7% in those classified as obese (Cook et al., 2008).

Although there does not appear to be a common unifying pathophysiological cause for all components of MetS, central obesity and insulin resistance appear to be the major drivers of this condition. The majority of obese individuals are insulin resistant but the correlation between obesity and insulin resistance is better for abdominal obesity/waist circumference than it is for overall BMI and better for whites than for African Americans. Moreover, weight loss following the feeding of low-calorie diets or following bariatric surgery rapidly leads to marked improvements in insulin sensitivity. However, the relationship between obesity and whole-body insulin resistance is not direct but appears to be mediated through increased circulating fatty acids and ectopic fat deposition particularly in IMCL in skeletal muscle (Fig. 27-2). Consumption of a very low-calorie diet in obese subjects for as little as five days has been shown to produce marked decreases in IMCL and enhanced insulin sensitivity without significant changes in body fat mass (Lara-Castro et al., 2008). It has been suggested that reductions in glucose import into skeletal muscle with IMCL result from inhibition of translocation of the glucose transporter GLUT-4 from cytosolic- to membrane-associated compartments through the action of IMCL metabolites such as diacylglycerol, long-chain fatty acid CoAs, ceramides, and oxidized lipids (Pan et al., 1997). Insulin resistance in muscle is accompanied by evidence of impaired mitochondrial function. However, it is unclear if this is a consequence of or contributor to IMCL (Lara-Castro and Garvey, 2008). Reduced glucose transport also occurs in insulin-resistant adipose tissue itself and the negative effects of obesity are exacerbated because reduced insulin signaling in adipocytes also enhances expression of hormone-sensitive and adipose triglyceride lipases to further increase the release of NEFA (Cornier et al., 2008). The relationship between liver steatosis and hepatic insulin resistance is less clear and the question of whether NAFLD is a cause or a consequence of hepatic insulin resistance remains unresolved (Cohen et al., 2011). Insulin resistance in liver leads to excess glucose production as the result of a reduced ability of insulin to suppress the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). This contributes to systemic hyperglycemia and increased pancreatic insulin production. Insulin resistance and steatosis are strongly correlated and interventions that lead to lower plasma insulin levels also decrease liver triglyceride content. Moreover, patients producing hepatic insulin as a result of metastatic insulin-secreting tumors develop steatosis in the surrounding hepatocytes. However, the suggestion that steatosis causes hepatic insulin resistance is contradicted by data from genetically manipulated mouse models where reduced fatty acid mobilization, reduced fatty acid oxidation, and defective choline synthesis are all associated with development of steatosis, but where hepatic insulin sensitivity is maintained (Cohen et al., 2011).

The dyslipidemia associated with MetS is believed to be a direct consequence of increased VLDL secretion by the liver. Increased serum triglycerides are generally associated with a change in HDL size and lipid composition, and reduction of serum HDL concentration as a result of increased clearance via the kidney. Several different mechanisms have been proposed to explain the rise in blood pressure associated with MetS. Insulin acts both directly as a vasodilator and secondarily to increase sodium resorption from the kidney. Evidence suggests that under conditions of insulin resistance, the vasodilatory effects of insulin are lost while the renal effect on sodium resorption is maintained. In addition, fatty acids can act directly to mediate vasoconstriction and both fatty acids and insulin can increase the activity of the sympathetic nervous system. Adipokines, such as leptin and resistin, have also been implicated in the pathogenesis of obesity-associated hypertension (Cornier et al., 2008).

Therapeutic Options for Managing Metabolic Syndrome

Since it is unclear that there is a unifying mechanism underlying the constellation of metabolic and physiological abnormalities that make up MetS, management can be problematic. Lifestyle modifications in the obese, including diets producing stable weight loss and long-term increased physical activity or bariatric surgery (discussed below), are of benefit in treating all the components of MetS, but suffer from limited compliance and significant risk of complications in the case of surgery. Therefore, routine clinical management of MetS has focused on pharmaceutical therapies for insulin resistance/hyperglycemia, dyslipidemia, and hypertension to reduce the risks of cardiovascular disease and type 2 diabetes.

Several classes of drugs are used to target insulin resistance. Metformin acts on the liver to reduce hepatic glucose production as a result of activation of the AMP kinase pathway (Boyle et al., 2010). Moreover, metformin is relatively nontoxic and has been shown to reduce progression from hyperglycemia to type 2 diabetes and the incidence of cardiovascular disease (Knowler et al., 2002; Ratner et al., 2005). Thiazolidinediones such as pioglitazone and rosiglitazone also improve insulin sensitivity and slow progression of diabetes in about 50% of patients as a result of activation of the transcription factor PPARγ in extrahepatic tissues and increasing circulating levels of adiponectin (Gerstein et al., 2006; Cho and Momose, 2008). However, increased insulin sensitivity is associated with an expansion of adipose tissue and significantly increased body weight because PPARγ regulates adipocyte differentiation. Moreover, a recently discovered adverse effect of thiazolidinediones is increased bone loss and an increased risk of osteoporosis, since PPARγ activation in bone inhibits osteoblastogenesis and stimulates accumulation of fat cells in bone marrow (Lecka-Czernik, 2010). Additional concerns have been raised regarding potential for increased cardiovascular problems in patients taking rosiglitazone (Palee et al., 2011).

Dyslipidemia associated with MetS is a major modifiable risk factor for cardiovascular disease. Increased triglycerides and low HDL levels are often accompanied by increased total and LDL cholesterol and LDL is a primary target for cholesterol-lowering therapy. Standard first-line therapy is statin inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA), the rate-limiting step in cholesterol biosynthesis, such as atorvastatin (Lipitor^®). These compounds improve overall lipid profiles by decreasing LDL concentrations 20% to 40%, increasing HDL 5% to 10%, and decreasing triglycerides 7% to 30% (McFarlane et al., 2002). Although generally well tolerated, atorvastatin results in muscle or joint pain in 5% of patients. Muscle pain can be an indication of rhabdomyolysis (muscle breakdown). In addition, liver injury as indicated by elevated serum values of liver enzymes such as alanine aminotransferase (ALT) has been reported in some users (Bakker-Arkema et al., 1996). Statins are often used in combination with bile acid sequestrants such as ezetimibe or niacin to further reduce LDL and triglycerides and raise HDL levels. In addition to statins, high doses of 2 to 4 g of fish oil omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce serum triglycerides by 20% to 40% (Cornier et al., 2008).

Control of hypertension is also the key to prevention of cardiovascular events. Many antihypertensive drugs are available and are taken chronically. The most commonly prescribed are adrenergic β-blockers, which inhibit sympathetic inputs to reduce cardiovascular output and slow heart rate. Despite substantial decreases in systolic and diastolic blood pressure, long-term prospective studies suggest that treated hypertensive men continue to have a much greater risk of stroke and coronary heart disease than normotensive men of the same age in the second decade of treatment (Deshmukh et al., 2008). This may be due to metabolic side effects, particularly increased serum triglycerides and lowering of HDL. In addition, diuretics are often given in combination with β-blockers. This can result in reductions of serum potassium and increased occurrence of gout in patients with marginal uric acid concentrations. Other frontline antihypertensive drugs are the angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors work on the renin–angiotensin system by preventing the conversion of angiotensin I to angiotensin II and reducing production of the hormone aldosterone. Aldosterone acts to reduce sodium and water excretion and is a direct vasoconstrictor. ACE inhibitors reduce arteriolar resistance, increase venous capacity, and increase cardiac output while increasing sodium excretion. ACE inhibitors in general have favorable effects on lipid profile.

Nonalcoholic Steatohepatitis (NASH)

As described above, ectopic fat deposition in the liver is strongly correlated with obesity and insulin resistance. Although NAFLD is not considered a core symptom of MetS, it is often a comorbidity. Fatty liver is very common being found in 30% of autopsies and in >80% of the obese. However, for reasons that remain unclear, in the majority of cases, steatosis is reversible and relatively asymptomatic. The disease progression of NAFLD is first to NASH, which is characterized by cell death, inflammation, and fibrosis, then to cirrhosis in which liver function is significantly impaired, and ultimately to hepatocellular carcinoma (Fig. 27-3) (Cohen et al., 2011). Only about 30% of individuals with NAFLD show evidence of progression of pathology to NASH and of these, only 20% to 30% progress further to cirrhosis within 10 years. Of those with NASH-induced cirrhosis, 4% to 27% ultimately develop liver cancer. NASH was first described by Ludwig et al. in 1980 in a group of obese adults without a history of alcohol abuse and has increased in prevalence with the obesity epidemic to about 2% to 3% of the US population. It is also increasingly observed in the pediatric population including cases in children as young as two years of age (Loomba et al., 2009). Although steatosis can be diagnosed noninvasively using ultrasound or imaging, improved methods for early detection of NASH are urgently required. Although elevated serum ALT values increase the likelihood of NASH, up to 59% of NASH patients had normal ALTs and at present, only liver biopsy can provide accurate diagnosis.

Our understanding of the molecular mechanisms whereby NAFLD pathology progresses is hampered by lack of an animal model that recapitulates all aspects of the human disease (Hebbard and George, 2011). Until recently, a widely held “two-hit” hypothesis held that progression of NAFLD to NASH requires initial development of steatosis followed by several possible second hits. These include oxidative stress resulting from lipid peroxidation and mitochondrial dysfunction and ER stress triggered by protein misfolding resulting from direct lipotoxicity of saturated fatty acids. In addition, bacterial overgrowth and increased gut permeability resulting from chronic consumption of high-fat diets can increase plasma endotoxin levels resulting in Kuppfer cell activation and inflammation. An initiating role for steatosis in NASH progression is supported by human studies of NAFLD heritability. NAFLD, NASH, and cirrhosis cluster in families and one genetic variant consistently associated with appearance of NAFLD is a missense mutation in the PNPLA3 (adiponutrin) gene. PNPLA3 has triglyceride hydrolase activity that is lost on mutation, consistent with the accumulation of liver fat. In addition, treatment with insulin sensitizers, bariatric surgery, and lifestyle modification (diet and exercise) resulting in weight loss and reduction of hepatic fat content improve NASH liver pathology (Cohen et al., 2011). More recently the two-hit hypothesis has been modified into a multiple interrelated hit theory as evidence has accumulated that factors derived from obese adipose tissue such as adipokines and the proinflammatory cytokine tumor necrosis factor (TNFα), activation of the endogenous immune system through Toll-like receptors, and ER stress can all increase hepatic fat accumulation in addition to producing inflammation (Hebbard and George, 2011; Tilg and Moschen, 2010). The development of necroinflammatory injury in NASH livers appears to depend on oxidative stress and TNF. Treatment with dietary antioxidants such as the glutathione precursor N-acetylcysteine and vitamin E has recently been shown to prevent increases in serum ALT, suppress hepatic production of TNF, and improve NASH pathology (Baumgardner et al., 2008a,b; Sanyal et al., 2010). Development of fibrosis subsequent to NASH appears to involve activation of hepatic stellate cells by the cytokine transforming growth factor β (TGFβ) and inappropriate secretion of matrix components, particularly collagen, as a result of regenerative wound-healing responses to chronic liver injury and proliferative regenerative responses also ultimately promote development of hepatocellular carcinomas (Dooley et al., 2009; Matsuzaki, 2009; Nejak-Gowen and Monga, 2011).

Alteration in Drug Pharmacokinetics and Metabolism in Obesity and NAFLD

Obesity and fatty liver disease can have significant effects on drug pharmacokinetics, metabolism, and therapeutic efficacy with the potential to result in adverse drug reactions (Hanley et al., 2010; Merrell and Cherrington, 2011).

The most significant change in drug pharmacokinetics associated with obesity is likely to be in volume of distribution (Vd), and this determines loading dose selection. Vd estimates the extent to which a drug distributes into extravascular tissues and this in turn will depend on the drug's physiochemical properties, binding to plasma proteins, and tissue blood flow. The Vd of lipid-soluble drugs that partition readily into adipose tissue is likely to be significantly increased in obesity because obese individuals have a larger fat compartment into which the drug can distribute. In contrast, Vd for hydrophilic drugs that do not readily partition into fat may be relatively unaffected (Hanley et al., 2010). For example, whereas the Vd for the highly lipophilic drug docetaxel is increased by more than 400 L in the obese, the Vd for the water-soluble drug daptomycin is increased by only 2 to 4 L. There are little data to suggest that obesity significantly alters drug binding to albumin or other plasma proteins. However, reductions in tissue blood flow and altered cardiovascular function have been observed in obesity and may further alter Vd. Increases in Vd in obesity may significantly alter drug efficacy. For example, the disposition of lipid-soluble oral contraceptives such as ethinyl estradiol have been shown to be altered in obesity and increased weight may be associated with increased risk of failure of contraception. In such circumstances drug loading dose should be adjusted by total body weight or BMI.

The major influence determining the steady-state plasma concentration of a drug in a maintenance dose regimen is clearance (CL). This in turn depends on rate of metabolism and expression of drug transporters. Obesity and NAFLD appear to have variable effects on hepatic phase I and II drug metabolism and on transporters. However, significant species differences in regulation of these enzymes and transporters and lack of appropriate animal models for NAFLD/NASH make extrapolation of much of the experimental data to the clinic problematic (Merrell and Cherrington, 2011). Obesity and NAFLD have been shown to increase expression of the cytochrome P450 enzyme CYP2E1 in both animal models and human clinical studies. CYP2E1 is involved in the metabolism of ethanol, solvents, and volatile anesthetics such as halothane and enflurane. In contrast, hepatic expression of CYP1A2 that metabolizes approximately 15% of therapeutic drugs including anticoagulants, antidepressants, antihypertensive drugs, and cyclooxygenase-2 inhibitors appears to be consistently suppressed. The effects of NAFLD/NASH on expression of other cytochrome P450 enzymes are inconsistent. However, increases have been observed in expression of other phase I enzymes including NAD(P)H quinone oxidoreductase, the mitochondrial form of epoxide hydrolase, and several aldehyde dehydrogenases in animal models of NAFLD. Less is known about the effects of NAFLD/NASH on drug conjugation and transport. Decreased expression of sulfotransferases has been reported in NASH patients, but effects on drug glucuronidation are inconsistent and glutathione conjugation appears mixed despite observations of GSH depletion in human NAFLD patients. Recent studies in experimental rat models of NAFLD suggest decreased expression of hepatic uptake transporters such as NTCP and the OATPs and increased expression of efflux transporters, such as the multidrug resistance-associated proteins Mrp2, Mrp3, and Mrp4 (Fischer et al., 2009; Lickteig et al., 2007). This was accompanied by a proportional shift in elimination of acetaminophen metabolites from bile to urine.

Drug elimination as measured by half-life is affected by both Vd and CL and thus may also be altered in obesity. Half-life is calculated using the following formula: t_1/2 = (ln 2 × Vd)/CL, and thus changes in both Vd and CL can influence drug half-life. For example, the t_1/2 of the antidepressant diazepam is markedly increased in obese subjects as a result of increased Vd even though CL is unchanged.

Endocrine Dysfunction in Obesity, Metabolic Syndrome, and NAFLD

A wide spectrum of endocrine disruption is associated with obesity and MetS. Obesity in pregnancy can result in many complications including gestational diabetes, pregnancy-associated hypertension, preeclampsia, and fetal abnormalities including neural tube defects, spina bifida, heart defects, and cleft palate (Kulie et al., 2011). In addition, delays in milk production and decreased duration of breast-feeding have been associated with obesity in women as a result of hormonal and metabolic effects on mammary gland development during pregnancy.

As discussed above, hyperglycemia resulting from systemic insulin resistance provokes a compensatory increase in insulin secretion from the pancreas in obese individuals. Hyperinsulinemia then appears to have secondary effects on other endocrine systems. For example, growth hormone (GH) secretion is dramatically suppressed by obesity in both adults and children, but can be reversed by weight loss (Kreitschmann-Andermahr et al., 2010). Mechanisms appear to involve direct feedback effects of insulin on the pituitary and a reduction in secretion of the endogenous GH-releasing peptide ghrelin that is produced by the stomach and hypothalamic centers. In addition, although reductions in GH lead to a decrease in hepatic synthesis and serum concentrations of total insulin-like growth factor (IGF-1) in the obese, paradoxically obesity results in a suppression of IGF-binding proteins and thus an increase in free IGF-1. Free IGF-1 can also exert a negative feedback on GH secretion. In addition to effects on the GH–IGF axis, hyperinsulinemia also appears to increase adrenal androgen production and reduce plasma concentrations of sex hormone–binding globulin (SHBG) in obese prepubertal girls (Burt Solorzano and McCartney, 2010). Increased serum concentrations of free androgens appear to explain, in part, why childhood obesity is associated with earlier pubertal development. Rodent studies of high-fat feeding have demonstrated accelerated vaginal opening that was reversed by both androgen receptor blockade and normalization of glucose homeostasis with metformin. Hyperandrogenization also appears to explain the increased incidence of polycystic ovary syndrome (PCOS) in obese adolescent girls with MetS, anovulatory cycles, and subfertility in obese women of childbearing age. Increased adipose tissue mass also results in increased estrogen production as a result of androgen aromatization in fat tissues. This may also contribute to accelerated puberty in girls. Surprisingly, in obese boys, data suggest that puberty may be delayed. This may also be related to increased aromatization of androgens in adipose tissue because negative feedback of estrogens at the level of the hypothalamic–pituitary axis may result in reduced luteinizing hormone secretion and reduced testosterone production (hypogonadotropic hypogonadism). In addition to suppression in GH and gonadotropin secretion, hypothyroidism is common in individuals with MetS. Reduced thyroid hormone concentrations may exacerbate NASH progression in the liver by increasing triglyceride synthesis, reducing fatty acid oxidation, and increasing hepatic cholesterol concentrations by reducing conversion to bile acids (Loria et al., 2009).

Obesity and Cancer Risk

Increased BMI is well known to be associated with significantly increased risk of a number of cancers. These include sex-steroid-dependent endometrial, breast, and prostate cancer, GI tract cancers such as esophageal adenocarcinoma, and colon cancer and renal cancer (Table 27-1). Several mechanisms have been proposed related to endocrine and metabolic disturbances associated with obesity (Roberts et al., 2010). As described above, systemic insulin resistance results in hyperinsulinemia and reduces plasma IGF-1-binding protein levels to increase free IGF-1 concentrations. Insulin and IGF-1 cross-talk through each other's receptors to stimulate cell proliferation via activation of MAP-kinase cascades resulting in increased phosphorylation of ERK and via activation of Wnt-β-catenin pathways. In addition, they exert antiapoptotic effects through PI-3 kinase pathways. Increased sex steroid concentrations in obesity promote growth of tumors in the mammary gland, endometrium, and prostate. Adipokines may also play a role in promotion of obesity-associated cancers. Leptin that is increased as fat mass increases is proproliferative, antiapoptotic, and proinflammatory and promotes new blood vessel formation (angiogenesis). In contrast, adiponectin that is suppressed in obesity has the opposite properties and is inversely associated with the presence of cancer. Additional potential associations between obesity and cancer may involve depletion of cellular antioxidant systems as a result of the low-grade chronic systemic inflammation that accompanies morbid obesity and the possibility that mesenchymal stromal cells arising from expanding white adipose tissue may be recruited to tumors to promote angiogenesis and drive tumor progression (Roberts et al., 2010).

The opposite of overfeeding is CR (also known as dietary restriction). Over the past two decades, CR has been repeatedly shown to increase life span and reduce age-related disease in comparison with ad libitum feeding in a wide variety of organisms including yeast, nematodes, fruit flies, fish, many rodent species, and dogs (Smith et al., 2010). Recently, Colman et al. (2009) have reported similar findings in rhesus monkeys and a multisite human randomized clinical research study is currently in progress funded by the National Institute on Aging (NIA): Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (the CALERIE study, http://calerie.dcri.duke.edu/index.html). Preliminary data suggest reproduction of many of the results from animal studies including reduced fat and lean mass, reduced insulin, reduced energy expenditure, lower core body temperature, and improved lipid profiles. It has been suggested that the increased health and longevity associated with CR is related to reduced energy flow, increased insulin sensitivity, and reduced inflammation (Ye and Keller, 2010). Studies in yeast, C. elegans, and Drosophila have suggested that the life span–enhancing effects of CR are mediated through activation of a family of histone deacetylases known as the sirtuins (Sir), which act as sensors of nutrient flux (Smith et al., 2010). Intensive studies are underway to identify CR mimetics that might have the same benefits as CR on long-term health and longevity without the necessity for imposed food restriction. Most work has focused on the grape polyphenol resveritol that has been shown to activate Sir2 and to mimic CR effects to increase life span in yeast, C. elegans, Drosophila, and fish in the absence of nutrient alteration. A second CR mimetic receiving significant attention is rapamycin, an inhibitor of the nutrient signaling mediator target of rapamycin (TOR).

Lifestyle Modification: Dieting and Exercise

As applied to body composition, dieting involves a plan or regimen to improve body composition. Trimming excess body fat generally requires reductions in total caloric intake, increases in the TEE (exercise or physical activity), and modifications in diet composition. This combined strategy is intended to reduce energy intake to a level low enough to drive the body to utilize stored fat as an energy source, thereby burning body fat.

Almost any commercially available diet plan on the market can achieve body weight loss and reduction of total fat mass. For example, people who use the Atkins diet, which is a diet high in protein and fat and very low in carbohydrates, definitely lose weight. The major problem is sustaining a healthy body composition. Most dieters return to their predieting weight and body composition (or worse) because they never achieve a true lifestyle change that meets their expectations. Comprehensive lifestyle changes that promote sustainability include two major and closely linked components: (1) learning to consume only the amount of calories from high-quality foods necessary to support basal body energy needs plus energy needs to maintain physical activity; and (2) selecting a reasonable physical activity plan that fits into the dieters’ overall lifestyle patterns. Sustaining healthy body composition after significant weight loss seems to occur only in those individuals who can find a way to limit their intake of a healthy diet that they find acceptable in terms of taste, costs, and ease (food availability and ease and speed of preparation), plus an exercise regime that is acceptable in terms of access (eg, equipment, facilities, walking trails), appropriateness (eg, age-related, intensity levels), and time (eg, duration required, timing within a workday). Thus, losing weight and getting a healthy body composition comes down to energy balance, that is, consuming less energy than needed to maintain a given body composition. Maintaining a health body composition requires that energy intake equals energy expenditure. Promoting health in the context of a healthy body composition can be best achieved by including a physical activity plan, and this usually leads to healthier muscle, improved insulin sensitivity, normalization of blood lipid profiles, and improved cardiovascular measures.

Determining the energy needs is the easiest part of a plan, whereas limiting caloric intake, increasing physical activity, and sustaining these components of a plan are more difficult. In terms of energy, 3500 cal is stored in 1 lb of fat. So to lose or take off that pound of fat, the body needs to be forced to “burn” 3500 cal from adipose tissue. That pound of fat was formed over time and under conditions in which calorie intake exceeded caloric output. The energy in food eaten can be “cost accounted” roughly as follows: (1) energy required to digest and absorb food; (2) energy utilized to support basal functions such as pumping blood and breathing; (3) energy for body functions other than basal functions such as walking and playing golf; and (4) nonutilized food calories such as food components not fully digested or absorbed. Most generally healthy people have similar energy expenditure needs as described in points 1, 2, and 4 above, although there clearly are individual differences. The energy expenditure of a body at rest is termed the BMR and it can be estimated by the Harris–Benedict equations. Energy expenditures also differ by age, gender, and body size (height and weight). For example, according to the Harris–Benedict equations, a man and a woman (each healthy and normal body composition) of age 66 years, weighing 160 lb, and 70 in tall would have a BMR of 1528 and 1372 cal, respectively. However, if they were each of age 18 years, their BMR would be 1854 and 1598 cal, respectively. No matter what a person's excess weight might be, there will always be the need for energy to meet the BMR. The energy needs of BMR could be met by diet or, in the case of overweight individuals, body energy stores such as fat. Because there are other nutrient needs besides energy (eg, nitrogen, amino acids, essential fatty acids, vitamins, minerals, and trace elements), an overweight individual will always have needs for a healthy diet, even for the short term, so fasting is usually not a long-term option to burn all excess stored body fat. Thus, to burn excess body fat, daily energy expenditure needs to exceed the energy expenditure of BMR and this comes mainly from physical activity.

The general public tends to overestimate the energy expenditure for various physical activities. It also finds it difficult to practically translate the often-recommended amount of physical activity (30 minutes of activity per day) into a daily regimen. Part of this is due to the difficultly in determining the energy expenditure amount, because the energy expended by an individual on 30 minutes of physical activity differs according to body weight, body composition, health, physical conditioning, and the activity itself (eg, walking, jogging at 4 miles/h, running a four-minute mile, or swimming a mile). In addition, overweight people are usually not accustomed to physical activity at the intensity level and duration needed to induce the body to burn body fat stores that lead to significant body fat reduction. This, when combined with the necessary changes in the diet composition and reductions in caloric intake, makes it difficult to lose body fat and more difficult to maintain a healthy body composition. The most common physical activity used in weight loss programs is walking. Walking 30 minutes at a rate of 4 miles/h for the 160-lb man or woman described above will burn approximately 180 cal. So if an overweight individual were to maintain the same caloric intake (and same diet) and just increase his or her activity level to 30 minutes of walking at 4 miles/h (a total of 2 miles per day), the calculated fat loss would be 1 lb every 20 days. If he or she also reduced the caloric intake by 180 cal a day and has the same walk schedule, he or she would reduce the time to lose 1 lb of weight to about 10 days. Thus, the way to reduce body fat (adipose tissue) is to consume less calories than expended (energy deficit) and the rate of fat loss is directly related to the level of the energy deficit (ie, caloric intake vs caloric expenditure).

Complicit in any plan to burn body fat stores is that some portion of the TEE must be met by fat stores. This requires a diet intake situation that: (1) provides fewer calories than required to meet BMR + any physical activity expenditure; (2) reduces or prevents lipogenesis; and (3) promotes lipolysis. There are several ways and several commercially available diet systems in which this can be accomplished. One of the most widely used diet systems, the Atkins diet, claims to accomplish this by increasing protein (and consequently fat) and limiting carbohydrates. Below the theory of this diet is presented as an illustration.

Following a meal containing an abundance of simple carbohydrates, blood glucose levels rise and glucose gets converted into glycogen by the liver and stored there for future energy use. Maximal glycogen storage is between about eight and 14 hours, depending on factors such as an individual's metabolism. As glucose enters cells, blood glucose concentrations would fall if not for the liver converting the glycogen back to glucose and releasing it back into the blood. This is a mechanism for maintaining glucose in the normal range between meals. Glucose is the body's energy source of choice. Use of glucose as the primary energy source seems to be prioritized by cell and organ type, with nerve cells having the highest priority. This means that if body glucose stores become scarce, the brain will be the last organ able to use glucose as its primary source. In this case, if another carbohydrate-containing meal is not consumed and blood glucose levels dropped to very low levels, lower priority organs (such as muscle) would need another source of energy and this source is fatty acids released from fat stores (lipolysis). Just like glycogen is the storage form for glucose, fat is the storage source for fatty acids and tissues can easily burn fatty acids when glucose is absent. As liver glycogen stores become minimal, amino acids are converted to glucose (gluconeogenesis). This can support nerve cell metabolism for a while, but eventually the brain will switch from burning pure glucose and start to utilize ketone bodies produced in the liver from fatty acids as an additional energy source. High ketone levels in the blood and tissues are known as ketosis.

Insulin has a major influence on carbohydrate, fat, and protein metabolism. Under conditions of adequate carbohydrate intake, insulin causes excess sugar not utilized as fuel to be stored as fat and prevents utilization of fat as an energy source. Thus, a high-carbohydrate diet tends to induce insulin secretion, which promotes carbohydrate energy storage as fat and tends to reduce the utilization of fat as an energy source. In theory, the low carbohydrate, high protein intake promoted in the Atkins diet forces the body to burn more fat. This would call for the body to switch from using pure carbohydrates for fuel to using more fat for fuel and the source of this fat is the adipose tissue. Thus, when insulin levels are normal, the body will begin to burn its own fat as fuel, thereby resulting in body weight loss.

Toxic Effects of Dieting

There are potential toxic effects associated with some diet plans. Dieting as described in this chapter is based on the use of a healthy diet that meets the daily nutrient needs of the body, but at a reduced caloric intake and with increased moderate physical activity. The overarching premise is to provide adequate nutrients for normal cellular function, while reducing caloric intake to a level that forces the use of fat stores as an energy source to meet the energy expenditure above the caloric intake. If the diet does not include all the required nutrients (an imbalanced diet), metabolism will suffer and with time this can result in health problems. This is true whether in the case of deficiency of specific nutrients (deficiency disorders such as anemia or osteoporosis) or toxicity caused by excesses of a particular nutrient (such as thyroid impairment, vitamin deficiencies, mental confusion). Some popular diet plans call for excess intake of a particular food and these can not only alter metabolism but also interfere with medications. For example, the popular grapefruit diet can lead to inhibition of drug-metabolizing enzymes such as the cytochrome P450 CYP3As that metabolize 60% of all therapeutic medications. This may increase drug concentrations to toxic levels, increase drug–drug interactions, and result in potential health problems (Ameer and Weintraub, 1997; Kiani and Imam, 2007).

Another potential adverse effect of dieting is known as the yo-yo effect or weight cycling. This occurs with repeated dieting interspersed with periods of no dieting. This is caused when a dieter starts one diet and loses a significant amount of body weight and body fat, but cannot maintain the diet and stops to return to the prediet routine. The fat and body weight are regained, often times to an even greater body fat. In fact, the yo-yo experience may actually result in a condition in which the dieter is more efficient in gaining weight. This results in the dieter selecting another diet plan, loss of weight, failure to maintain the diet, and return to overweight or obese conditions. There are often periods of depression and fatigue associated with this cycling behavior and the end results are extreme emotional and physical ramifications. Whether the yo-yo dieter has other health issues remains ill-defined and controversial.

Drug Therapy for Weight Loss

In addition to the diet plans described above, many overweight individuals turn to drug therapy to help lose body weight. Appetite suppressants, for example, sympathomimetics such as diethylpropion, attempt to lessen the psychological motivation for food, usually by acting on central nervous system appetite control centers, such as those in the hypothalamus (Guaraldi et al., 2011). Although sympathomimetics can be used for long periods of time, their appetite-reducing effects tend to decrease after a few weeks in many people. Thus, appetite suppressants are often used in the early stages of a weight loss program. People are likely to lose weight while taking sympathomimetics, but the weight loss is generally temporary without modifications in diet composition, eating behavior, and physical activity. Short-term use is usually accompanied by minor side effects such as thirst, irritability, constipation, stomach pain, dizziness, dryness of mouth, heightened sense of well-being, headache, irritability, nausea, nervousness or restlessness, trembling or shaking, and trouble sleeping. However, long-term use of appetite suppressants often times leads to more serious side effects: intracerebral hemorrhage, acute dystonia, myocardial injury, psychosis, cerebral arteritis, cardiac arrhythmias, heart valve damage, and even fatal pulmonary hypertension. These side effects have led to the withdrawal of several such products from the market. Drug interactions are also known to occur, especially with high blood pressure medicine, stimulants, MAO inhibitors (eg, furazolidone, linezolid, phenelzine, selegiline, tranylcypromine), any other weight loss medicine, and decongestants such as are commonly found in over-the-counter cough and cold medicines.

Surgical Interventions

Surgery is another avenue to improve body composition in obesity. One of the most radical surgical treatments is the class operations known as bariatric surgeries. The end goal is to limit food intake by reducing the capacity of the stomach, but also having patients feel satiated. Bariatric surgery is actually a term that includes several surgical procedures (such as sleeve gastrectomy, gastric plication, gastric banding, gastric bypass surgery); all are aimed at helping obese patients lose weight. Weight loss is achieved by resecting and linking the small intestines to a small stomach pouch (gastric bypass surgery), removal of a portion of the stomach (sleeve gastrectomy), or reducing the size of the stomach with an implanted medical device (gastric banding) or sutures (gastric plication). These procedures are generally credited with significant long-term loss of body fat and body weight, which leads to improvement of secondary conditions caused by obesity, including type 2 diabetes, risk of cardiovascular disease, and the rate of mortality (Robinson, 2009).

These operations are most commonly used to treat morbid obesity and the comorbidities associated with it. Thus, bariatric surgery may be recommended for people with a BMI >40. These procedures have also been used successfully with obese individuals with BMI 30 to 40, especially when there are serious coexisting medical conditions such as hypertension, impaired glucose tolerance, diabetes mellitus, hyperlipidemia, and obstructive sleep apnea. Most bariatric procedures result in rapid weight loss, which is also associated with gallstones, and many surgeons prefer to remove the gallbladder at the time of bariatric surgery. Malabsorption and nutritional deficiency can occur because of reduced absorptive area. This can reduce calcium and vitamin absorption. Poor calcium absorption can occur because calcium transporters are located in areas of the intestine (duodenum) that may be removed with bariatric surgery. This can cause metabolic bone disease (osteopenia) and secondary hyperparathyroidism that increase in bone turnover. Combined, these conditions decrease bone mass and increase risk of fracture. Other deficiencies including iron and micronutrients such as vitamin B₁₂, fat-soluble vitamins, thiamine, and folate are common. Many patients will need to take a daily multivitamin pill for life to compensate for reduced absorption of essential nutrients. Because patients cannot eat a large quantity of food, physicians typically recommend a diet that is relatively high in protein and low in fats and alcohol.

Liposuction is another surgical procedure widely used to improve body composition by physically and surgically removing body fat. It is the most common “plastic surgical procedure” in the United States. However, there are significant risks with this procedure and these are mainly associated with: (1) the aggressiveness with which the procedure is performed, especially the amount of tissue sucked from the body; (2) the venues in which the procedures are performed; and (3) the amount of anesthesia used to sedate patients during increasingly lengthy procedures. The mortality rate of the late 1990s was approximately 20 per 100,000 or 1 per 5000 cases (de Jong and Grazer, 2001).

Health Insurance and Obesity

Obesity is not considered an illness for most insurance purposes. However, obesity can affect the cost of health insurance because as a group, obese people have a significantly greater risk of cardiovascular disease, hypertension, type 2 diabetes, and other health issues than lean people. Thus, insurance companies factor obesity into the cost of first-time insurance purchasers. Furthermore, people who are already insured may unknowingly not have sufficient insurance to cover health problems associated with obesity. Several health insurance companies use BMI as a measure of obesity and use BMI to compute disease risk and health insurance premiums. Obesity can result in high premiums and in the case of morbidly obese individuals, insurers may decline their application. Obesity is also regarded by insurance companies as a substantial risk for both life and disability policies.

Mortality statistics for life insurance were the earliest indicator that the cost of obesity to the individual was decreased life span and increased illness, particularly diseases affecting the cardiovascular and musculoskeletal systems. The prevalence of coronary heart disease rises with increases in the BMI in both men and women. Hypertension and diabetes in the obese add further to the risks of vascular disease. Cigarette smoking also greatly augments the health risks of obesity in both sexes.

The risk of death and medical problems increase with the degree or severity of obesity (as indicated by fat mass or BMI). The type of obesity (as indicated by body shape or fat distribution) is another aspect of obesity considered by insurance companies. Abdominal obesity has been positively correlated with the risk of heart disease and stroke. Thus, some insurance companies set rates in part on fat distribution. Disability insurance rates are also affected by body composition, as cardiovascular disease or musculoskeletal illness associated with obesity greatly increases the chances of disabilities. All of these factors are used in decision making as to whether to insure an individual and the cost of premiums. Clearly, costs increase proportionally with the degree of obesity.

Changing the Environment: Family and Community Approaches to Healthy Eating and Physical Activity

The development of obesity within an individual, a community, or a country is complex and the central cause(s) or reason(s) underlying the rapid rise in obesity in the United States and the world is not well understood. The end results in terms of body composition and secondary medical problems associated with obesity are better understood than the root causes of the obesity epidemic. One factor, however, that has received much attention relates to basic practices that were common in past decades when the general population was leaner, but are lacking now when obesity is so prevalent.

Prior to 1970, the average BMI was 25.1 for men and 24.9 for women in the United States. Physical education (PE) classes were a regular feature of school curriculums; most meals were prepared at home using fresh produce, meats, and dairy products. School lunches were prepared at schools. It was common for children to walk or ride bicycles to school and to participate in games requiring physical activity during school recess and after school and on weekends. There were no computer games and fast food restaurants did not supply such a large proportion of the daily total calories. In the 1990s and 2000s, there are few schools with PE classes and fewer meals cooked from fresh components consumed at home and the lifestyle of today's children and adults is far more sedentary than that prior to 1970. As a consequence, by 2002, average BMI for US men had risen to 27.8 and average BMI for US women to 28.1.

One approach to fighting the obesity issue is to bring back many of those practices used in the past. There are initiatives to establish community gardens, build community walking and riding trails, and teach people cooking and shopping skills that lead to healthier meal preparation. School systems are starting to return to PE classes on a regular basis and remove high-density foods and drinks from vending machines. Although these efforts have been increasing in effort throughout the United States, it is still too early to confirm their effectiveness in reversing the obesity trend.

Food security and access to quality foods is an important issue throughout the United States, regardless of whether in rural America or in the inner city. In many areas there is ready access only to convenience food stores where there is a lack of fresh vegetable and meats and the prices are higher than in a conventional supermarket. The type of food available is poor quality and energy dense, which leads to obesity. These areas have been termed “food deserts.” Providing access to higher-quality fresh food to people living in these areas will improve nutrition and when combined with education on how to select and prepare the food and linked to some form of physical activity, it is hoped that body composition and health will improve in these areas.

Food Labels

The Food and Drug Administration (FDA) is responsible for assuring that foods sold in the United States are properly labeled. This applies to foods produced domestically, as well as foods from foreign countries. The Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Fair Packaging and Labeling Act are the federal laws governing food products under FDA's jurisdiction. The Nutrition Labeling and Education Act (NLEA), which amended the FD&C Act, requires most foods to bear nutrition labeling. The FDA requires food labels that bear nutrient content claims and certain health messages to comply with specific requirements.

Food labeling is required for most prepared foods, such as breads, cereals, canned and frozen foods, snacks, desserts, drinks, etc. Nutrition labeling for raw produce (fruits and vegetables) and fish is voluntary. Dietary supplements are a special category of products under the general umbrella of foods, but which has separate labeling requirements. “Functional foods” or “nutraceuticals” are regulated by FDA under the authority of the FD&C Act, but they are not specifically defined by law.

Food labels can be an important factor to help consumers in their food choices that can help prevent obesity and other diseases. Federal law requires that a minimal amount of information be listed on food packaging, including ingredients and nutrition data. The FDA monitors labeling language for such issues as fat, protein, carbohydrate, and other nutrient contents and the purported ability of a particular food to prevent medical problems. Suspicious or doubtful claims or misleading statements about nutrition and health benefits on food packages can be challenged by the FDA and companies that receive warning letters have 15 days to inform the agency of corrective action. Although there has been a formal process by which a health claim can be made, foods generally are not permitted to make disease-fighting claim. The types of claims often challenged by the FDA include warding off maladies such as arthritis, cancer, and heart disease.

The Patient Protection and Affordable Care Act of 2010 establishes requirements for nutrition labeling of standard menu items for chain restaurants, similar retail food establishments, and chain vending machine operators. The most important information that must be provided for standard menu items is the number of calories in each standard menu item and a statement on the menu that puts the calorie information in the context of a recommended total daily caloric intake. In addition to restaurant menus, food sold from vending machines operated by persons who own or operate 20 or more vending machines must disclose the amount of calories in a clear and conspicuous manner.

Governmental and Corporate Issues

There has been increasing pressures from local, state, and federal governments to regulate various aspects of food as a means of promoting health and reducing obesity and the secondary consequences of obesity. Food labeling is just one example of government intervention, whereby food processors and restaurants must provide a measure of nutrient and/or caloric content. New York City was the first to pass a law requiring calorie counts to be posted next to prices on menus in some restaurants so consumers would also know the “caloric cost” of each food selection, with the hope that they will make healthy food choices. California became the first state to prohibit restaurants from using “artery-clogging trans fats” in preparing their food. Airlines and the FAA are dealing with complaints from passengers being “infringed on” by overlapping obese passengers and obese passengers complaining about abuse taken from leaner passengers. In an effort to reduce insurance costs and improve work performance, there is also a trend for the business community to set standards associated for overweight and obese workers in a manner similar to that employed for smokers. Civil rights advocates and others are concerned that there is a growing impetus for government intervention and one wonders if the time will come when “big brother” mandates what and how much one can eat.