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).
Effects of excess calories (energy) on fat morphology under conditions leading to metabolic syndrome (left) or following stimulation of adipocyte differentiation and hyperplasia by thiazolidinedione treatment/in knockout mice incapable of normal responses to hypoxia (HIF-1α −/−)/in knockout mice incapable of normal extracellular matrix production (SPARC−/−, Coll 6−/−) (right).
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).
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).
Pathogenesis of metabolic syndrome.
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.
Progression of nonalcoholic fatty liver disease (NAFLD). ROS, Reactive oxygen species; ER stress, Endoplasmic reticulum stress.
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: t1/2 = (ln 2 × Vd)/CL, and thus changes in both Vd and CL can influence drug half-life. For example, the t1/2 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).
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).
Table 27-1Estimated Risk Ratios* for Cancer in Relation to BMI ||Download (.pdf) Table 27-1 Estimated Risk Ratios* for Cancer in Relation to BMI
|CANCER TYPE ||MEN ||WOMEN |
|Colon cancer ||1.24 ||1.09 |
|Gallbladder cancer ||— ||1.59 |
|Leukemia ||1.08 ||1.17 |
|Malignant melanoma ||1.17 ||— |
|Multiple myeloma ||1.11 ||1.11 |
|Esophageal adenocarcinoma ||1.52 ||1.51 |
|Renal cancer ||1.24 ||1.34 |
|Thyroid cancer ||1.33 ||1.14 |
|Prostate cancer ||1.03 ||— |
|Postmenopausal breast cancer ||— ||1.12 |
|Endometrial cancer† ||— ||1.73 |