Chapter 20. Obesity

• α-MSH α-Melanocyte–stimulating hormone
• ACTH Adrenocorticotropic hormone
• AGRP Agouti-related peptide
• ARC Arcuate nucleus of the hypothalamus
• BDNF Brain-derived neurotrophic factor
• BMI Body mass index
• CCK Cholecystokinin
• CCK-1R CCK 1 receptor
• CSF Colony-stimulating factor
• FFA Free fatty acid
• FTO Fat mass- and obesity-associated gene
• GI Gastrointestinal
• GLP1 Glucagon-like peptide 1
• IL-6 Interleukin 6
• LepR Leptin receptor
• LHA Lateral hypothalamic area
• MC4R Melanocortin-4 receptor
• MCP-1 Monocyte-chemoattractant protein-1
• NAFLD Nonalcoholic fatty liver disease
• NCEP National Cholesterol Education Program
• NEGR1 Neuronal growth regulator 1
• NHANES National Health and Nutrition Examination Survey
• NHLBI National Heart, Lung, and Blood Institute
• NTRK2 Neurotrophic tyrosine kinase, receptor, type 2
• NPY Neuropeptide Y
• OSA Obstructive sleep apnea
• PAI-1 Plasminogen-activated inhibitor
• PC-1 Proconvertase 1
• PCOS Polycystic ovarian syndrome
• POMC Pro-opiomelanocortin
• PVN Paraventricular nucleus
• PYY Peptide YY
• RYGB Roux-en-Y gastric bypass
• SH2B1 Adapter protein 1
• SOS Swedish Obese Subjects
• SIM1 Single minded 1
• STAT Signal transducer and activator of transcription
• T2DM Type 2 diabetes mellitus
• TMEM18 Transmembrane protein 18
• TNF Tumor necrosis factor-α
• WHO World Health Organization

Definition

Obesity and overweight categories have been defined by examining longitudinal study data that associate a given weight with future adverse health effects. The currently accepted surrogate measure of body fatness is body mass index (BMI) which is measured as weight in kilograms divided by height in meters squared. For adults, a BMI <18.5 kg/m2 is underweight, 18.5 to 24.9 kg/m2 is healthy weight, 25.0 to 29.9 kg/m2 is overweight, and ≥30 kg/m2 is obese. For children and adolescents, a BMI between the 85th and 95th percentile for age and sex is considered at risk of overweight, and BMI at or above the 95th percentile is considered overweight or obese.

However, BMI does not account for ethnic differences in skeletal structure or musculature. Body frame size varies dramatically by race/ethnicity from small-framed East Asian adults to larger framed Pacific Islanders. Moreover, conventional cut-points for adult overweight (BMI ≥25 kg/m2) and obesity (BMI ≥30 kg/m2) do not correspond to similar absolute or relative metabolic risk in all ethnic group. As a result, the World Health Organization (WHO) and International Obesity Task Force proposed a lower BMI cut-point to define obesity in South and East Asian adults: 23 kg/m2 for overweight and 25 kg/m2 for obesity.

Prevalence and Projections

National surveys performed by the Centers for Disease Control and Prevention in the United States have found a significant increase in the prevalence of overweight and obesity over the past 30 years. In 2003 to 2004, according to data from the National Health and Nutrition Examination Survey (NHANES), 32.2% of adults were obese. Trends among adults have been tracked by repeat NHANES surveys, showing that the percent of overweight or obese have climbed from 47.0% in 1976 to 1980 to 66.2% in 2003 to 2004, and the prevalence of obesity alone has more than doubled from 15.0% to 32.9% overall. The prevalence of obesity was 45.0% among non-Hispanic blacks, 36.8% among Mexican Americans, and 30.6% among non-Hispanic whites.

The trends in obesity have been most striking among children and adolescents with two- to threefold increases in rates over the past three decades in all age groups. In the NHANES 2003 to 2004 survey, a total of 17.1% of US children and adolescents were overweight (BMI ≥95th percentile). Among children aged 2 to 5 years, the obesity prevalence increased from 5% in the 1976 to 1980 NHANES to 12.4% in 2003 to 2006 NHANES. Similarly, the prevalence in age 6 to 11 years increased from 6.5% to 17.0%, and for ages 12 to 19 years increased from 5% to 17.6% in the most recent national survey.

While the United States leads most of the world with high prevalence of overweight and obesity, these conditions are becoming more prevalent worldwide even in developing countries. In China, overweight prevalence in adults increased from 14.6% to 21.8% between 1992 and 2002, with greatest increases seen among men, urban residents, and high-income groups. In India, the prevalence of overweight ranged from 9.4% in rural men to 38.8% in urban women in 2003 to 2005.

Globally, according to a pooled analysis, in 2005 there were an estimated 937 million (95% CI, 922-951 million) overweight adults and 396 million (388-405 million) obese adults. Using conservative projections, by 2030 the number of overweight adults was estimated to be 1.35 billion and 573 million obese individuals without adjusting for secular trends. The authors warned that if recent secular trends continue unabated, the absolute numbers may total 2.16 billion overweight and 1.12 billion obese adult individuals. Among US residents, projections forecast that by 2030, 86.3% adults will be overweight or obese (51.1%) with black women (96.9%) and Mexican American men (91.1%) being most affected. Wang et al estimate that by 2048, all American adults would become overweight or obese, and in children, the prevalence of overweight (BMI ≥95th percentile) would almost double to 30%.

Possible Explanations for the Increased Obesity Rates

Several hypotheses have been proposed to explain the rapid rise in overweight/obesity in developed and developing countries. The simple explanations start with changes in lifestyle behaviors, primarily the lack of regular physical activity and increased caloric intake that tip the energy balance equilibrium. The reality of the factors promoting the obesity epidemic is clearly more complex and involves multiple layers of determinants including social norms and values, several sectors of influence from governmental to media to the food/entertainment industries, behavioral settings including the work/home/neighborhood environment, to individual factors that include genetic, socioeconomic, cultural, and psychosocial factors. In a novel social network analysis of the Framingham cohort, investigators found that weight status (gain, loss, or stability of weight) for an individual was highly influenced by his/her friends and family extending out to three degrees of separation. A multifaceted approach will be required to meaningfully curb the obesity epidemic globally.

Regulation of Food Intake and Energy Expenditure

Obesity is an increase of energy stored as fat that occurs when caloric intake exceeds caloric expenditure. What causes this imbalance is less clear, but recent advances in our understanding of the physiological systems responsible for the maintenance of energy stores in response to variable access to nutrition and demands for energy expenditure have provided some insights into the pathophysiology of obesity. The physiological system controlling food intake and energy expenditure is composed of (1) long-term and short-term afferent signals that allow for sensing the energy status of the individual; (2) integrating brain centers, most importantly within the hypothalamus, where the level of the efferent response is determined; and (3) efferent signals including those regulating the intensity of hunger and the level of energy expenditure.

One common misconception is that this physiological system is dedicated to the prevention of obesity. Instead this system's essential role is in the prevention of starvation (ie, ensuring adequate energy intake to compensate for the energy requirements of basal metabolism, physical activity, growth, and reproduction). As a result, this physiological system is more strongly biased toward prevention of energy deficiency rather than excess storage.

Informing the Brain of the Energy Status: Leptin and Short-Term Gastrointestinal Signals

Leptin.

The major afferent signal allowing the brain to sense the level of energy stores is the hormone leptin. Discovered in 1994, this cytokine-like 167 amino acid protein is released by adipocytes. Under basal conditions the circulating levels of serum leptin are correlated with fat mass (r = 0.8) and decrease after weight loss. Decreasing leptin levels inform the brain of diminishing fat storage resulting from negative energy balance. This results in compensatory effects on appetite and energy expenditure, aimed at replenishing the stores and reestablishing energy balance. The role of leptin is best understood from the phenotype of rare cases of humans with complete leptin deficiency. Despite early-onset, extremely severe obesity, these patients show behaviors and physiological signs of starvation. This includes hyperphagia, decreased immune function, and hypogonadotropic hypogonadism. The latter reflects deficiency of the leptin signal informing the brain that sufficient energy stores are available for reproduction. Hormonal replacement of leptin-deficient patients corrects all these abnormalities, abolishing the hyperphagia leading to normalization of weight and maturation of the reproductive axis.

Leptin's action is mediated by the leptin receptor (LepR). This receptor is a member of the class I cytokine receptor family which also includes the growth hormone, prolactin and erythropoietin receptors (see Chapter 1). These receptors have a single transmembrane domain and homodimerize upon binding of the ligand. Leptin binding to LepR leads to phosphorylation of the JAK2 receptor-associated kinase followed by recruitment and phosphorylation of the signal transducer and activator of transcription STAT3. Upon activation STAT3 dimerizes and translocates to the nucleus, where it activates transcription of target genes. The LepR is expressed in almost every tissue but only one of five isoforms, LepRb, contains the STAT3 recruitment domain. This isoform is expressed specifically in leptin-responsive brain regions.

In summary, leptin functions as a long-term signal of energy balance by informing the brain of changes in the level of energy stored as fat. A perceived decrease in leptin levels increases the amount of food consumed and minimizes energy expenditure. Leptin levels do not change with meals, and leptin does not acutely change meal size.

Signals from the Gastrointestinal Tract.

In addition to leptin, which represents a long-term adiposity signal, a number of other hormones, most of which are secreted by the gastrointestinal (GI) system, regulate appetite on a short-term basis (ie, in response to a meal) (Table 20–1). These hormones act on satiation (the feeling of fullness that contributes to the decision to stop eating) rather than on satiety (the prolongation of the interval until hunger or a drive to eat reappears). Some of these hormones have been shown to act on the same brain centers as leptin does. Altered secretion of or response to these GI hormones may directly contribute to the pathogenesis or the maintenance of obesity. Cholecystokinin (CCK) is secreted by duodenal I cells into the bloodstream. Its secretion is stimulated by the presence of fat and protein in the duodenum. CCK stimulates gut motility, contraction of the gallbladder, pancreatic enzyme secretion, gastric emptying, and acid secretion. CCK acts locally, stimulating vagal sensory nerves through the CCK 1 receptor (CCK-1R) and informs the brain that fat and proteins are being processed and will soon be absorbed. This message is conveyed to the hypothalamus via the hindbrain. Circulating CCK levels increase after meals and infusion of a CCK-1R agonist (CCK33), to postprandial levels, suppresses food intake. Conversely, infusion of a CCK-1R antagonist increases calorie intake. CCK is also a proximal mediator of the broader satiation process, attenuating meal-induced changes of more distal GI hormones, such as ghrelin and peptide YY (PYY).

Glucagon-like peptide 1 (GLP1) is a 30 amino acid peptide derived from the proglucagon gene. GLP1 is secreted into the bloodstream by the intestinal L-cells of the ileum and colon in response to the presence of nutrients in the lumen. GLP1 has a very short half-life (2 minutes), and is degraded by dipeptidyl peptidase-4. It increases insulin secretion in a glucose-dependent manner, decreases glucagon secretion, increases beta cell mass, inhibits gastric emptying, and decreases food intake. GLP1 is thought to signal through the hindbrain via stimulation of the GLP1 receptor (GLP1R) on the vagus nerve.

PYY, a 36 amino acid peptide is released into the bloodstream by intestinal endocrine L-cells of the distal gut (ileum and colon) after food ingestion and in response to the presence of fat in the lumen. PYY3-36, the major form of circulating PYY, binds to the hypothalamic NPY-Y2 receptor and reduces food intake. Obese individuals have lower PYY levels after a test meal than nonobese controls.

Ghrelin, a 28 amino acid octanoylated peptide, is secreted into the bloodstream by endocrine cells lining the fundus of the stomach. Ghrelin secretion is stimulated by fasting, increases preprandially, and is suppressed by food intake. Ghrelin is orexigenic, increasing food intake when administered peripherally, and acts in part by directly modulating the activity of the NPY (neuropeptide Y)/AGRP (agouti-related peptide) neurons in the arcuate nucleus of the hypothalamus.

Central Integration of Energy Homeostasis Signals

The major challenge of adapting food intake to energy expenditure lies in the discontinuous availability of the first and the continuous and variable levels of the second required for survival, growth, and reproduction. The current prevailing model is that the concentration of circulating adiposity signals, primarily leptin, influences the response to short-term satiation signals thereby allowing for sufficient energy intake to maintain a constant level of stored energy. Genetic studies in mice and humans have outlined several critical neuronal populations and circuits that translate information provided by afferent circulating hormonal signals into neural responses that regulate appetite and energy expenditure. The primary locus for the integration of peripheral signals that influence energy balance is the hypothalamus (Figure 20–1). Specifically, two adjacent groups of neurons in the arcuate nucleus (ARC) of the hypothalamus, characterized by their production of specific neuromediators, act as the primary site in the brain for receiving the humoral signals that reflect body energy status. The AGRP/NPY neurons are orexigenic. They are inhibited by leptin and their activity is also modulated by GI hormones, such as ghrelin and PYY. The pro-opiomelanocortin (POMC) neurons are anorexigenic and are activated by leptin. In these neurons, POMC is processed by the specific proteases proconvertase-1 and proconvertase-2 to the anorexigenic neuropeptide α-melanocyte–stimulating hormone (α-MSH). Interactions between these neurons within the ARC allows for cross talk and modulation of the neuronal output.

These first-order neurons send projections to second-order neurons in other regions of the hypothalamus, specifically the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA), as well as to the hindbrain. Both α-MSH and AGRP act on a common receptor, the melanocortin-4 receptor (MC4R) expressed on PVN neurons. α-MSH binds to and activates the melanocortin 4 receptor (MC4R) and by competing with α-MSH for the MC4R, AGRP inhibits MC4R-bearing neurons. The MC4R neurons then innervate neurons in other areas of the hypothalamus and brain stem to produce an integrated inhibition of appetite and increase in energy expenditure.

Leptin Resistance in Obesity

While recombinant leptin can correct the exceptionally rare cases of obesity due to genetic leptin deficiency, all other obese patients have leptin levels that are proportional to their fat mass. In addition, recombinant leptin injections in obese patients do not lead to weight loss. Therefore, despite the presence of elevated leptin concentrations, which should reduce food intake and body fat, obese patients appear to be insensitive or resistant to leptin. Both genetic and environmental factors have been shown to contribute to this leptin resistance, and a number of specific alterations in the downstream leptin effector pathways have been suggested to participate in this obesity-associated leptin resistance. Understanding the nature of this leptin resistance may allow for the development of novel obesity treatments but its molecular basis is probably heterogenous and different in each patient.

Genetics of Obesity

Excess caloric intake and the tendency toward a more sedentary lifestyle are certainly to blame for the increased prevalence of obesity, but individuals exposed to the same environmental pressures have different levels of vulnerability. Indeed, genetic epidemiologic studies, such as twin studies and adoption studies have implicated genetic factors in the susceptibility to obesity. These studies have shown that genetic factors account for 40% to 70% of the population variation in BMI and that the heritability of obesity increases with its severity. Emphasis has, therefore, now shifted from the question of whether human obesity has a genetic component to how many and which genetic variants underlie this susceptibility. While the majority of genes that contribute to the predisposition to obesity are still unknown, both common genetic variants, with small effects on the BMI at the level of the population, and single gene defects, causing Mendelian forms of obesity, have been described.

Large and comprehensive genome-wide association studies find that a number of common genetic variants are associated with obesity (Table 20–2). These variants are near genes that are expressed in the central nervous system further suggesting a role for an alteration of central regulatory pathways in the pathogenesis of obesity. However, since these variants are not located within the protein-coding regions of these genes, the exact mechanism by which they predispose to obesity remains to be elucidated. More importantly, the individual as well as the combined effects of these common variants only explain a small fraction of the inherited variability in obesity (10%-20%), suggesting that rare variants may contribute more significantly to the genetic predisposition to this condition.

Indeed a number of single gene defects that cause human obesity have been uncovered. These defects have provided more insight into the genetic predisposition and pathophysiology of obesity. Certain mutations can cause obesity as part of a complex syndrome, in which developmental phenotypes are prominent (Table 20–3). However, most single gene defects causing Mendelian forms of obesity are in genes of the leptin-melanocortin system (Table 20–4). The description of patients with these mutations has both provided insight into the genetic predisposition to obesity and has confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans. Mutations in leptin and the LepR cause severe obesity associated with hypogonadotropic hypogonadism. Mutations in POMC cause severe obesity, due to absent synthesis of α-MSH in the hypothalamus, and neonatal adrenal insufficiency, due to lack of ACTH production in the anterior pituitary gland. These recessive syndromes are extremely rare. In contrast, mutations in MC4R represent the most common genetic cause of severe obesity accounting for 2.5% of all cases. Patients who carry such mutations do not have specific clinical or biological characteristics that differentiate them from other patients with severe obesity; genetic testing is the only reliable method to identify these patients. At present, such testing is not recommended since the presence or absence of one of these mutations carries no specific implications for the clinical management of these patients.

Mechanism Underlying Obesity Complications: Adipose Tissue as an Endocrine Organ

The massive public health burden of obesity is due to the psychological, behavioral, and medical consequences of this chronic increase in adipose tissue mass. Pathophysiological mechanisms underlying the complications of obesity include the psychological and behavioral responses to the image projected in a society in which obesity is considered cosmetically unattractive, the mechanical effects of increased adipose mass on weight-bearing joints as well as other organs, and the metabolic consequences of increased circulating free fatty acids (FFAs).

It is also now clear that the adipose cell is not simply dedicated to inertly storing energy as triglycerides and releasing free fatty acids and glycerol during periods of increased energy needs. In addition to leptin, described earlier, which informs the brain of the level of energy stores, adipose cells secrete a number of factors, known as adipokines, which can play a role in the pathophysiology of obesity and its complications (Figure 20–2). For example, adiponectin is an abundant plasma protein, structurally related to the complement 1q family, that is secreted exclusively from adipose tissue. Adiponectin circulates in serum as a range of multimers from low-molecular-weight trimers to high-molecular-weight (HMW) dodecamers. Circulating levels of adiponectin are negatively correlated with fat mass and are reduced in obesity. Adiponectin improves whole-body insulin sensitivity through its receptor-mediated actions on the muscle and the liver. Specifically, adiponectin stimulates fatty acid oxidation and glucose uptake in skeletal muscle and suppresses glucose output in the liver.

In addition, a number of factors secreted by adipose tissue, particularly in the context of obesity, are proinflammatory cytokines. It is now generally accepted that obesity is a state of chronic, low-grade inflammation. These inflammatory molecules exert their effects through both paracrine and endocrine pathways. Initially thought to be secreted by adipocytes, most of these factors are actually produced by other cells such as macrophages, which infiltrate the adipose tissue in obesity. Tumor necrosis factor-α (TNF-α) was the first adipose-derived factor suggested to represent a link between adiposity and the insulin resistance associated with type 2 diabetes. Released by activated macrophages, which infiltrate expanding adipose tissue in obesity, this cytokine has been strongly implicated in the pathogenesis of insulin resistance, directly impairing insulin signaling in hepatocytes and adipocytes. Other adipokines involved in obesity-associated inflammation include interleukin 6 (IL-6), monocyte-chemoattractant protein-1 (MCP-1), plasminogen-activated inhibitor (PAI-1), and colony-stimulating factor (CSF).

Metabolic Complications of Obesity: Insulin Resistance and Type 2 Diabetes

Hyperinsulinemia is characteristically associated with obesity. This hyperinsulinemia is linked to insulin resistance (ie, the decrease in insulin-stimulated glucose utilization, which increases proportionally with fat mass). One of the major consequences of this obesity-associated insulin resistance is the requirement for increased insulin secretion. While the majority of obese individuals can secrete sufficient insulin to accommodate the insulin-resistant state, this increased burden on the insulin-producing pancreatic beta cells increases the susceptibility to failure, resulting in type 2 diabetes (T2DM) in genetically predisposed individuals. Indeed, over 80% of T2DM patients are obese. In comparison with a normal-weight individual, BMI greater than 40 (obesity class 3) in a person under 55 years of age increases the risk of T2DM by 18.1-fold in men and 12.9-fold in women. Classification as overweight (BMI 25-30) increases the prevalence of T2DM three- to fourfold in both men and women under 55 years of age. The relative risks associated with excess body weight are weaker in older individuals but are still present (eg, about twofold for overweight and three- to sixfold for obesity class 3).

The increased rate of T2DM is the most worrisome public health issue linked to the increased rates of obesity. The anticipated health outcomes such as premature heart disease, peripheral vascular disease, renal failure, blindness, are deeply concerning and place this among our highest contemporary public health priorities. Some recent studies have estimated that the current generation of American youth will be the first to exhibit shorter life spans than their parents, because of the impact of obesity on T2DM.

Dyslipidemia

Obesity is associated with dyslipidemia characterized by increased levels of very low density lipoprotein (VLDL) cholesterol, triglycerides, and total cholesterol as well as a decrease in HDL cholesterol and an increase in small dense LDL particles. The difference in serum triglyceride concentrations between individuals with BMI less than 21 and those with BMI greater than 30 is about 65 mg/dL (in women) and 62 to 118 mg/dL (in men, depending on age). For HDL cholesterol, each 1-unit BMI change is associated with an HDL-cholesterol decrease of 1.1 mg/dL for young men and 0.7 mg/dL for young women. All of the components of this obesity-associated dyslipidemia have been shown to be atherogenic and play a major role in the development of atherosclerosis and cardiovascular disease in obese individuals.

Weight loss and exercise, even if they do not result in normalization of body weight, can improve this dyslipidemia and thus reduce CVD risk. In addition, obese individuals should be targeted for intense lipid-lowering therapy, when necessary.

The Metabolic Syndrome

The concept of the metabolic syndrome was first introduced in 1923 by Kylin who described the clustering of hypertension, hyperglycemia, and gout as a syndrome. Reaven and others redefined this concept as the insulin resistance syndrome, a clustering of glucose intolerance, high triglycerides, low HDL cholesterol, and hypertension. The two most consistent characteristics of persons with the syndrome are insulin resistance and central abdominal obesity. There is strong epidemiologic and pathophysiologic evidence linking visceral adiposity with insulin resistance and diabetes, with dyslipidemia, hyperinsulinemia, and decreased fibrinolysis as possible mediators of the relationship between visceral fat and type 2 diabetes and cardiovascular disease risk.

The earliest attempt to create a definition for this constellation of metabolic disorders was by the WHO wherein an individual with glucose intolerance or insulin resistance was required to have two or more criteria (elevated triglycerides, low HDL cholesterol, high BMI or waist-hip ratio, hypertension, or microalbuminuria) in order to be categorized as having metabolic syndrome. The next attempt at a clinical definition was by the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III in 2001 that required three or more of the following criteria for the metabolic syndrome definition: high fasting glucose, high triglycerides, low HDL, high blood pressure or waist circumference. More recently, the International Diabetes Federation (IDF) proposed further refined criteria that require central abdominal obesity, and two more criteria as proposed by the NCEP. The IDF criteria were the first ones to account for the heterogeneity of body size among different ethnic groups, and the committee recommended different waist circumference cut-points based on ethnicity with a revised definition for South Asians, Chinese, and Japanese recommending similar waist circumference cut-points in men (≥90 cm) and in women (≥80 cm) compared to the European cut-points of ≥94 cm in men and ≥80 cm in women. More recently, the utility of the metabolic syndrome has been questioned, given that there are no treatment options available, and rather each cardiometabolic risk factor (eg, blood pressure control) is treated individually.

Cardiovascular Complications

Higher cardiovascular disease risk has been linked to visceral adiposity with several distinct mechanisms including inflammation, thrombosis, hyperglycemia, atherogenic dyslipidemia, and adipocytokines (hormones and proteins exclusively secreted by adipose tissue). Obesity has been implicated as one of the major risk factors for hypertension, heart failure, and coronary heart disease. Other cardiovascular conditions associated with obesity include peripheral arterial disease and atrial fibrillation.

Altered hemodynamics of obesity due to increases in total blood volume, systemic arterial pressure, and cardiac output increase the workload of the heart and can lead to adverse effects on cardiovascular structure and function. Overweight individuals develop left ventricular dilation and hypertrophy and left atrial enlargement. These structural abnormalities increase the risk of heart failure and of atrial fibrillation. In the Framingham Heart Study, every 1-unit increase in BMI increased the risk of heart failure by 5% in men and 7% in women. However, several recent studies have also found an obesity-cardiovascular disease paradox where overweight and obese individuals with existing heart failure or heart disease have a lower risk of mortality than those who are underweight or normal weight. These findings suggest that obese individuals may have the metabolic reserve to withstand high catabolic needs as exist in heart failure.

Pulmonary Complications

Obesity can cause alveolar hypoventilation, increased pulmonary blood volume, and mechanical effects on the respiratory system. Obstructive sleep apnea (OSA) is associated with obesity and other features of the metabolic syndrome, with the most closely correlated factor being hypertension. Intermittent upper airway obstruction results in hypoxia, sympathetic nervous system surges, and airway inflammation. Patients with sleep apnea have higher risk of systemic and pulmonary hypertension, heart failure, dysrhythmias, myocardial infarction, and overall mortality. Mechanisms that have been implicated in the development of cardiovascular disease in obstructive sleep apnea include increased oxidative stress and inflammation that cause endothelial dysfunction. While significant weight loss can improve OSA and associated metabolic features, mechanical therapies used to treat sleep apnea with constant positive airway pressure have not been found to improve hypertension or other metabolic features.

Gastrointestinal Complications

Nonalcoholic fatty liver disease (NAFLD) is commonly seen with insulin resistance or obesity and includes a spectrum of liver disease from steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and rarely, cirrhosis. Fat accumulates within the liver with recruitment of inflammatory cells and fibrosis. The prevalence of NAFLD in obesity is 50% to 85%. Risk factors associated with NAFLD besides obesity include advancing age, visceral adiposity, atherogenic dyslipidemia, and hypertension. NAFLD is the leading cause of chronic liver disease in the United States, and given the high rates of obesity, approximately one-third of US adults are estimated to have NAFLD.

NAFLD has been observed in overweight children and adolescents with prevalence estimated at 6% to 23% in population-based US samples. In children, there seems to be a clear male predominance for NAFLD which suggests distinct pathophysiologic mechanisms for NAFLD between adults and children. Histologic criteria have been proposed to distinguish adult (type 1) and pediatric (type 2) NAFLD. In a large study of German children, the three main factors that contributed to NAFLD by principal components analysis included an insulin resistance/visceral adiposity factor, a body fat distribution/CRP factor, and lastly a sex steroid hormone factor.

Other GI complications of abdominal obesity include gastroesophageal reflux disease and hiatal hernia. Both of these conditions can cause erosive mucosal changes in the lower esophagus leading to higher risk of Barrett esophagus.

Reproduction and Gynecologic Complications

Obesity has been associated with both female and male infertility. In women, polycystic ovarian syndrome (PCOS) is the main cause of female infertility associated with obesity. Women with PCOS have ovulatory dysfunction and hyperandrogenemia. PCOS is reviewed in more detail in Chapter 13. In men, obesity can cause reduced sperm counts and motility. Hormonal changes with obesity and associated metabolic disorders may lead to poor sperm production. Obesity is also associated with erectile dysfunction through proinflammatory mechanisms and decreased testosterone levels.

Cancer

Several cancers have been linked to obesity, including breast, endometrial, colorectal, prostate, and renal cell carcinomas. Putative mechanisms for breast and endometrial cancer include higher circulating levels of unopposed estrogen and ovarian hyperandrogenism, causing higher levels of testosterone and lower levels of luteinizing hormone. The relationship between obesity and colon cancer is stronger in men than women.

Screening and Prevention of Complications

Periodic health screening with a measurement of both height and weight to calculate BMI is recommended by many organizations including the National Heart, Lung, and Blood Institute (NHLBI), the US Preventive Services Task Force, and the WHO. Furthermore, the NHLBI also recommends waist circumference measurement routinely to find persons at risk of metabolic complications of overweight. Patients who are found to be in the overweight or obese categories of BMI are recommended to have other risk factors checked as well, including blood pressure, fasting glucose, and lipoprotein levels.

Therapeutic Approaches for Weight Loss

Several behavioral, pharmacologic, and surgical therapies for weight loss have been studied in randomized controlled trials. In general, behavioral interventions with lifestyle change including diet and exercise and pharmacologic therapies work to achieve modest amounts of weight loss while patients adhere to the intervention. Recommended for more severe levels of obesity, bariatric surgery does lead to larger amounts of weight loss, but requires lifelong medical supervision and management of the side effects associated with the surgery.

Behavior, Diet, and Exercise Therapies

While many believe that long-term weight loss with lifestyle change is not achievable by most patients, longitudinal studies have found that 20% of overweight individuals are successful at weight loss defined as losing at least 10% of initial body weight and maintaining the loss for at least 1 year. Individuals enrolled in the National Weight Control Registry have lost an average of 33 kg and maintained the loss for more than 5 years. Behaviors that have been most effective for long-term weight loss include high levels of physical activity (∼1 hour/day), self-monitoring weight, eating a low-calorie, low-fat diet, eating breakfast regularly, and maintaining a consistent eating pattern throughout the week.

Dietary Interventions.

Several commercial, fad, and therapeutic dietary interventions exist for weight loss. Recent dietary trends have focused on relative changes in macronutrient composition of the diet to achieve weight loss, such as low-fat or low-carbohydrate diets. Few have been rigorously tested, and no trials have long-term outcome data (defined as the occurrence of comorbidities or mortality). A recent randomized trial comparing four popular diets (Atkins, Zone, Weight Watchers, and Ornish diet) found that weight change did not significantly differ between participants assigned to any of the four diets, and better dietary adherence predicted higher amount of weight loss. The most difficult diets for participants to adhere to were the very low-fat diet (Ornish) and the low-carbohydrate diet (Atkins). In a recent meta-analysis of five dietary trials for weight loss, low-carbohydrate non–energy-restricted diets were found to be as effective as low-fat, energy-restricted diets for weight loss up to 1 year. The weighted mean difference in weight loss was greater in the low-carbohydrate diets (−3.3 kg, 95% CI −5.3 to −1.4 kg, p = 0.02) in the first 6 months, but there was no difference in weight loss after 12 months between the two types of diet (−1.0 kg, 95% CI −3.5 to 1.5 kg, p = 0.15). Additionally, there was no clear benefit on cardiovascular risk factors with either type of diet.

Physical Activity Interventions.

The Institute of Medicine recommends physical activity of 60 min/d for most days of the week for weight loss and/or control of weight. The recommendations for heart disease prevention are 30 min/d of moderate-intensity physical activity on most days per week, or at least 150 min/wk.

In a systematic review of trials of an aerobic physical activity intervention in overweight populations, body weight decreased significantly in seven of nine trials, but weight increased in two trials. The two studies that combined diet with aerobic training had the largest amounts of weight loss (>10 kg each). However, these trials were uncontrolled and of relatively short duration. It remains unclear whether long-term lifestyle change with physical activity can decrease risk of cardiovascular disease or mortality in obese individuals.

Pharmacologic Intervention/CAM.

Weight loss medications have had mixed results with most delivering modest amounts of short-term weight loss, often associated with many undesirable side effects. Currently there are four main categories of weight loss medications approved by the FDA: adrenergic agents, serotonergic agents, combination of both adrenergic/serotonergic agents, and lipase inhibitors. Other medications available for off-label use include some antidepressants and anticonvulsant agents. A majority of available obesity treatments work by suppressing appetite centrally. One approved medication, orlistat, prevents digestion and absorption of dietary fat by inhibiting the gut enzyme lipase. There are several different sites of action under investigation for potential medications including specific neurotransmitter targets to decrease appetite and/or promote satiety, endocannabinoid system antagonists and opioid receptor targets to reduce food intake, and peripheral targets that work at the level of the intestines or pancreas to modulate food intake.

Table 20–5 shows specific medications in each category, the amount of weight loss reported in trials compared to placebo from a recent review and meta-analysis, and the common side effects of each agent. The two most frequently studied weight loss medications, sibutramine and orlistat, have had the best efficacy in longer- term trials (52 weeks). However, both of these drugs are associated with significant side effects which limit their use. Other antiobesity medications in the drug development pipeline include lorcaserin, an agonist that targets serotonin 2C receptors to cause satiety, and a multiple monoamine reuptake inhibitor, tesofensine, that reduces reuptake of norepinephrine, serotonin, and dopamine to cause appetite suppression. An endocannabinoid receptor antagonist, rimonabant, was successful in producing modest weight loss and improving metabolic complications. However, adverse central nervous system side effects of rimonabant including depression and anxiety precluded introduction of this drug into clinical practice.

Complementary and alternative medications such as herbs, vitamins, nutritional supplements, and meal replacement therapies are commonly used by the general public for weight loss. However the efficacy and safety of these herbal remedies has not been well studied. A recent meta-analysis of trials found that compounds containing ephedra, Cissus quadrangularis, ginseng, bitter melon, and zingiber had some short-term efficacy with weight loss with mostly mild adverse effects. However, longer-term randomized controlled trials are needed to prove efficacy and safety.

Bariatric Surgery

Surgical treatment for weight loss has been performed for the past 50 years, and these procedures are increasing in popularity. Approximately 20,000 weight-loss surgeries were performed in 1995 and over 140,000 were done in 2004, a sevenfold increase. There are three main types of bariatric surgeries: restrictive, malabsorptive, and those that have both a restrictive and a malabsorptive component. Purely restrictive surgeries include horizontal gastroplasty, vertical banded gastroplasty, silastic ring vertical gastroplasty, and adjustable gastric banding. Purely malabsorptive surgeries include the oldest of all bariatric procedures, the jejunoileal bypass, biliopancreatic diversion, duodenal switch, and long limb gastric bypass. The combination of restrictive and malabsorptive surgical procedure is the most commonly used bariatric surgery worldwide, the Roux-en-Y gastric bypass procedure (RYGB), which involved stapling the upper stomach into a small 30-mL pouch and attaching it to the jejunum bypassing the lower stomach and duodenum. This procedure can be done with an open surgical approach, or now more commonly with a laparoscopic approach.

Several studies have examined the effects of different types of bariatric surgeries on various outcomes including weight loss, comorbid disease, complication rates, and mortality. There are very few randomized controlled trials comparing different surgical procedures, so most of the outcomes data come from case series, prospective cohort analyses, or nonrandomized trials. The largest and longest double cohort study to date is the Swedish Obese Subjects (SOS) study in which obese adults who voluntarily underwent bariatric surgery were matched to a control group of medically treated patients. After 10 years of follow-up of 1703 participants, those treated with surgery had a 16% weight loss compared to 2% in the controls (p <0.001). They compared the different types of bariatric surgery approaches in this study and found that those who had gastric bypass lost more weight than those who received banding procedures or the vertical banded gastroplasty.

An earlier meta-analysis determined the effect of bariatric surgery on weight loss, mortality, and four comorbid diseases including diabetes, hyperlipidemia, hypertension, and sleep apnea. The mean excess weight loss was 61.2% (58.1%-64.4%), highest in those who had the biliopancreatic diversion or duodenal switch (70.1%) and lowest in those who underwent gastric banding (47.5%). Operative mortality within 30 days of the surgery was 0.1% for purely restrictive procedures and 0.5% for gastric bypass, and 1.1% for biliopancreatic diversion or duodenal switch procedures. Type 2 diabetes resolved in approximately 77% of patients after surgery, hyperlipidemia improved in 70%, hypertension resolved in 62%, and obstructive sleep apnea resolved in 86%.

Much attention has focused on determining the mechanisms involved in the dramatic weight loss associated with bariatric surgery. Previous hypotheses that restrictive procedures reduce the quantity of food ingested at any one time, malabsorptive procedures cause wasting of fat calories, with RYGB employing a combination of both mechanisms, have not been supported by studies. More recent thinking attributes weight loss after bariatric procedures to a substantial decline in hunger and increase in satiety that is regulated through neuroendocrine mechanisms and gut hormones such as ghrelin and PYY. The effect of RYGB surgery on ghrelin levels is controversial since some studies have found increased levels, no change, or decreased levels after surgery. These inconsistent results may be explained by the timing of ghrelin sampling after surgery. After purely restrictive surgeries, ghrelin levels increase, which may help explain the more dramatic weight loss observed following RYGB vs purely restrictive surgeries. PYY levels rise to those of a nonobese person following vertical banded gastroplasty. However, with RYGB, there is an early exaggerated response in PYY secretion, approximately two- to fourfold greater than that observed in lean, obese, or gastric banded patients, which may contribute to the sustained weight loss seen with this type of procedure.

Defining appropriate patient criteria to minimize risks and maximize the benefits from bariatric surgery have been debated. Some studies have concluded that surgical intervention is more effective for weight loss and control of comorbid diseases than nonsurgical treatments in patients with a BMI ≥40 kg/m2. In 2004, with extensive scientific input, the National Coverage Advisory Committee panel concluded that bariatric surgery could be offered to Medicare beneficiaries with BMI ≥35 kg/m2 who have at least one comorbid disease associated with obesity and have been unsuccessful previously with medical treatment of obesity. Other criteria for patient selection proposed by leading associations include adequate patient commitment with medical follow-up and use of dietary supplements, no other reversible endocrine disorders causing obesity, no current substance abuse, and no severe psychiatric illness.

Interventions with Efficacy in Children

Several studies have investigated behavioral and lifestyle intervention programs for pediatric weight loss. Most randomized controlled trials of overweight children and adolescents have found positive, but small- to -moderate effects, of combined lifestyle interventions on BMI. Family-based behavioral weight loss programs have produced larger effects that persist for several months of follow-up. Less is known about the long-term safety and efficacy of pharmacologic agents for treatment of pediatric obesity.