In a world where food supplies are intermittent, the ability to store energy in excess of what is required for immediate use is essential for survival. Fat cells, residing within widely distributed adipose tissue depots, are adapted to store excess energy efficiently as triglyceride and, when needed, to release stored energy as free fatty acids for use at other sites. This physiologic system, orchestrated through endocrine and neural pathways, permits humans to survive starvation for as long as several months. However, in the presence of nutritional abundance and a sedentary lifestyle, and influenced importantly by genetic endowment, this system increases adipose energy stores and produces adverse health consequences.
Definition and Measurement
Obesity is a state of excess adipose tissue mass. Although often viewed as equivalent to increased body weight, this need not be the case—lean but very muscular individuals may be overweight by numerical standards without having increased adiposity. Body weights are distributed continuously in populations, so that choice of a medically meaningful distinction between lean and obese is somewhat arbitrary. Obesity is therefore more effectively defined by assessing its linkage to morbidity or mortality.
Although not a direct measure of adiposity, the most widely used method to gauge obesity is the body mass index (BMI), which is equal to weight/height2 (in kg/m2) (Fig. 77-1). Other approaches to quantifying obesity include anthropometry (skinfold thickness), densitometry (underwater weighing), CT or MRI, and electrical impedance. Using data from the Metropolitan Life Tables, BMIs for the midpoint of all heights and frames among both men and women range from 19 to 26 kg/m2; at a similar BMI, women have more body fat than men. Based on data of substantial morbidity, a BMI of 30 is most commonly used as a threshold for obesity in both men and women. Large-scale epidemiologic studies suggest that all-cause, metabolic, cancer, and cardiovascular morbidity begin to rise (albeit at a slow rate) when BMIs are ≥25, suggesting that the cutoff for obesity should be lowered. Most authorities use the term overweight (rather than obese) to describe individuals with BMIs between 25 and 30. A BMI between 25 and 30 should be viewed as medically significant and worthy of therapeutic intervention, especially in the presence of risk factors that are influenced by adiposity such as hypertension and glucose intolerance.
Nomogram for determining body mass index. To use this nomogram, place a ruler or other straight edge between the body weight (without clothes) in kilograms or pounds located on the left-hand line and the height (without shoes) in centimeters or inches located on the right-hand line. The body mass index is read from the middle of the scale and is in metric units. (Copyright 1979, George A. Bray, MD; used with permission.)
The distribution of adipose tissue in different anatomic depots also has substantial implications for morbidity. Specifically, intraabdominal and abdominal subcutaneous fat have more significance than subcutaneous fat present in the buttocks and lower extremities. This distinction is most easily made clinically by determining the waist-to-hip ratio, with a ratio >0.9 in women and >1.0 in men being abnormal. Many of the most important complications of obesity such as insulin resistance, diabetes, hypertension, hyperlipidemia, and hyperandrogenism in women, are linked more strongly to intraabdominal and/or upper body fat than to overall adiposity (Chap. 242). The mechanism underlying this association is unknown but may relate to the fact that intraabdominal adipocytes are more lipolytically active than those from other depots. Release of free fatty acids into the portal circulation has adverse metabolic actions, especially on the liver. Whether adipokines and cytokines secreted by visceral adipocytes play an additional role in systemic complications of obesity is an area of active investigation.
Data from the National Health and Nutrition Examination Surveys (NHANES) show that the percentage of the American adult population with obesity (BMI >30) has increased from 14.5% (between 1976 and 1980) to 33.9% (between 2007 and 2008). As many as 68% of U.S. adults aged ≥20 years were overweight (defined as BMI >25) between the years of 2007 and 2008. Extreme obesity (BMI ≥40) has also increased and affects 5.7% of the population. The increasing prevalence of medically significant obesity raises great concern. Obesity is more common among women and in the poor, and among blacks and Hispanics; the prevalence in children is also rising at a worrisome rate.
Physiologic Regulation of Energy Balance
Substantial evidence suggests that body weight is regulated by both endocrine and neural components that ultimately influence the effector arms of energy intake and expenditure. This complex regulatory system is necessary because even small imbalances between energy intake and expenditure will ultimately have large effects on body weight. For example, a 0.3% positive imbalance over 30 years would result in a 9-kg (20-lb) weight gain. This exquisite regulation of energy balance cannot be monitored easily by calorie-counting in relation to physical activity. Rather, body weight regulation or dysregulation depends on a complex interplay of hormonal and neural signals. Alterations in stable weight by forced overfeeding or food deprivation induce physiologic changes that resist these perturbations: with weight loss, appetite increases and energy expenditure falls; with overfeeding, appetite falls and energy expenditure increases. This latter compensatory mechanism frequently fails, however, permitting obesity to develop when food is abundant and physical activity is limited. A major regulator of these adaptive responses is the adipocyte-derived hormone leptin, which acts through brain circuits (predominantly in the hypothalamus) to influence appetite, energy expenditure, and neuroendocrine function (see below).
Appetite is influenced by many factors that are integrated by the brain, most importantly within the hypothalamus (Fig. 77-2). Signals that impinge on the hypothalamic center include neural afferents, hormones, and metabolites. Vagal inputs are particularly important, bringing information from viscera, such as gut distention. Hormonal signals include leptin, insulin, cortisol, and gut peptides. Among the latter is ghrelin, which is made in the stomach and stimulates feeding, and peptide YY (PYY) and cholecystokinin, which is made in the small intestine and signal to the brain through direct action on hypothalamic control centers and/or via the vagus nerve. Metabolites, including glucose, can influence appetite, as seen by the effect of hypoglycemia to induce hunger; however, glucose is not normally a major regulator of appetite. These diverse hormonal, metabolic, and neural signals act by influencing the expression and release of various hypothalamic peptides [e.g., neuropeptide Y (NPY), Agouti-related peptide (AgRP), α-melanocyte-stimulating hormone (α-MSH), and melanin-concentrating hormone (MCH)] that are integrated with serotonergic, catecholaminergic, endocannabinoid, and opioid signaling pathways (see below). Psychological and cultural factors also play a role in the final expression of appetite. Apart from rare genetic syndromes involving leptin, its receptor, and the melanocortin system, specific defects in this complex appetite control network that influence common cases of obesity are not well defined.
The factors that regulate appetite through effects on central neural circuits. Some factors that increase or decrease appetite are listed. NPY, neuropeptide Y; MCH, melanin-concentrating hormone; AgRP, Agouti-related peptide; α-MSH, α-melanocyte-stimulating hormone; CART, cocaine- and amphetamine-related transcript; GLP-1, glucagon-related peptide-1; CCK, cholecystokinin.
Energy expenditure includes the following components: (1) resting or basal metabolic rate; (2) the energy cost of metabolizing and storing food; (3) the thermic effect of exercise; and (4) adaptive thermogenesis, which varies in response to long-term caloric intake (rising with increased intake). Basal metabolic rate accounts for ∼70% of daily energy expenditure, whereas active physical activity contributes 5–10%. Thus, a significant component of daily energy consumption is fixed.
Genetic models in mice indicate that mutations in certain genes (e.g., targeted deletion of the insulin receptor in adipose tissue) protect against obesity, apparently by increasing energy expenditure. Adaptive thermogenesis occurs in brown adipose tissue (BAT), which plays an important role in energy metabolism in many mammals. In contrast to white adipose tissue, which is used to store energy in the form of lipids, BAT expends stored energy as heat. A mitochondrial uncoupling protein (UCP-1) in BAT dissipates the hydrogen ion gradient in the oxidative respiration chain and releases energy as heat. The metabolic activity of BAT is increased by a central action of leptin, acting through the sympathetic nervous system that heavily innervates this tissue. In rodents, BAT deficiency causes obesity and diabetes; stimulation of BAT with a specific adrenergic agonist (β3 agonist) protects against diabetes and obesity. BAT exists in humans (especially neonates), and although its physiologic role is not yet established, identification of functional BAT in many adults using PET imaging has increased interest in the implications of the tissue for pathogenesis and therapy of obesity.
The Adipocyte and Adipose Tissue
Adipose tissue is composed of the lipid-storing adipose cell and a stromal/vascular compartment in which cells including preadipocytes and macrophages reside. Adipose mass increases by enlargement of adipose cells through lipid deposition, as well as by an increase in the number of adipocytes. Obese adipose tissue is also characterized by increased numbers of infiltrating macrophages. The process by which adipose cells are derived from a mesenchymal preadipocyte involves an orchestrated series of differentiation steps mediated by a cascade of specific transcription factors. One of the key transcription factors is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that binds the thiazolidinedione class of insulin-sensitizing drugs used in the treatment of type 2 diabetes (Chap. 344).
Although the adipocyte has generally been regarded as a storage depot for fat, it is also an endocrine cell that releases numerous molecules in a regulated fashion (Fig. 77-3). These include the energy balance–regulating hormone leptin, cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, complement factors such as factor D (also known as adipsin), prothrombotic agents such as plasminogen activator inhibitor I, and a component of the blood pressure–regulating system, angiotensinogen. Adiponectin, an abundant adipose-derived protein whose levels are reduced in obesity, enhances insulin sensitivity and lipid oxidation and it has vascular-protective effects, whereas resistin and RBP4, whose levels are increased in obesity, may induce insulin resistance. These factors, and others not yet identified, play a role in the physiology of lipid homeostasis, insulin sensitivity, blood pressure control, coagulation, and vascular health, and are likely to contribute to obesity-related pathologies.
Factors released by the adipocyte that can affect peripheral tissues. PAI, plasminogen activator inhibitor; TNF, tumor necrosis factor; RBP4, retinal binding protein 4.
Although the molecular pathways regulating energy balance are beginning to be illuminated, the causes of obesity remain elusive. In part, this reflects the fact that obesity is a heterogeneous group of disorders. At one level, the pathophysiology of obesity seems simple: a chronic excess of nutrient intake relative to the level of energy expenditure. However, due to the complexity of the neuroendocrine and metabolic systems that regulate energy intake, storage, and expenditure, it has been difficult to quantitate all the relevant parameters (e.g., food intake and energy expenditure) over time in human subjects.
Role of genes versus environment
Obesity is commonly seen in families, and the heritability of body weight is similar to that for height. Inheritance is usually not Mendelian, however, and it is difficult to distinguish the role of genes and environmental factors. Adoptees more closely resemble their biologic than adoptive parents with respect to obesity, providing strong support for genetic influences. Likewise, identical twins have very similar BMIs whether reared together or apart, and their BMIs are much more strongly correlated than those of dizygotic twins. These genetic effects appear to relate to both energy intake and expenditure.
Whatever the role of genes, it is clear that the environment plays a key role in obesity, as evidenced by the fact that famine prevents obesity in even the most obesity-prone individual. In addition, the recent increase in the prevalence of obesity in the United States is far too rapid to be due to changes in the gene pool. Undoubtedly, genes influence the susceptibility to obesity in response to specific diets and availability of nutrition. Cultural factors are also important—these relate to both availability and composition of the diet and to changes in the level of physical activity. In industrial societies, obesity is more common among poor women, whereas in underdeveloped countries, wealthier women are more often obese. In children, obesity correlates to some degree with time spent watching television. Although the role of diet composition in obesity continues to generate controversy, it appears that high-fat diets may promote obesity when combined with diets rich in simple, rapidly absorbed carbohydrates.
Additional environmental factors may contribute to the increasing obesity prevalence. Both epidemiologic correlations and experimental data suggest that sleep deprivation leads to increased obesity. Changes in gut microbiome with capacity to alter energy balance are receiving experimental support from animal studies, and a possible role for obesigenic viral infections continues to receive sporadic attention.
Specific genetic syndromes
For many years, obesity in rodents has been known to be caused by a number of distinct mutations distributed through the genome. Most of these single-gene mutations cause both hyperphagia and diminished energy expenditure, suggesting a physiologic link between these two parameters of energy homeostasis. Identification of the ob gene mutation in genetically obese (ob/ob) mice represented a major breakthrough in the field. The ob/ob mouse develops severe obesity, insulin resistance, and hyperphagia, as well as efficient metabolism (e.g., it gets fat even when ingesting the same number of calories as lean litter mates). The product of the ob gene is the peptide leptin, a name derived from the Greek root leptos, meaning thin. Leptin is secreted by adipose cells and acts primarily through the hypothalamus. Its level of production provides an index of adipose energy stores (Fig. 77-4). High leptin levels decrease food intake and increase energy expenditure. Another mouse mutant, db/db, which is resistant to leptin, has a mutation in the leptin receptor and develops a similar syndrome. The ob gene is present in humans where it is also expressed in fat. Several families with morbid, early-onset obesity caused by inactivating mutations in either leptin or the leptin receptor have been described, thus demonstrating the biologic relevance of the leptin pathway in humans. Obesity in these individuals begins shortly after birth, is severe, and is accompanied by neuroendocrine abnormalities. The most prominent of these is hypogonadotropic hypogonadism, which is reversed by leptin replacement in the leptin-deficient subset. Central hypothyroidism and growth retardation are seen in the mouse model, but their occurrence in leptin-deficient humans is less clear. To date, there is no evidence that mutations in the leptin or leptin receptor genes play a prominent role in common forms of obesity.
The physiologic system regulated by leptin. Rising or falling leptin levels act through the hypothalamus to influence appetite, energy expenditure, and neuroendocrine function and through peripheral sites to influence systems such as the immune system.
Mutations in several other genes cause severe obesity in humans (Table 77-1); each of these syndromes is rare. Mutations in the gene encoding proopiomelanocortin (POMC) cause severe obesity through failure to synthesize α-MSH, a key neuropeptide that inhibits appetite in the hypothalamus. The absence of POMC also causes secondary adrenal insufficiency due to absence of adrenocorticotropic hormone (ACTH), as well as pale skin and red hair due to absence of α-MSH. Proenzyme convertase 1 (PC-1) mutations are thought to cause obesity by preventing synthesis of α-MSH from its precursor peptide, POMC. α-MSH binds to the type 4 melanocortin receptor (MC4R), a key hypothalamic receptor that inhibits eating. Heterozygous loss-of-function mutations of this receptor account for as much as 5% of severe obesity. These five genetic defects define a pathway through which leptin (by stimulating POMC and increasing α-MSH) restricts food intake and limits weight (Fig. 77-5). The results of genomewide association studies to identify genetic loci responsible for obesity in the general population have so far been disappointing. More than 10 replicated loci linked to obesity have been identified, but together they account for less than 3% of interindividual variation in BMI. The most replicated of these is a gene named FTO, which is of unknown function, but like many of the other recently described candidates, is expressed in the brain. Since the heritability of obesity is estimated to be 40–70%, it is likely that many more loci remain to be identified.
Table 77-1 Some Obesity Genes in Humans and Mice |Favorite Table|Download (.pdf)
Table 77-1 Some Obesity Genes in Humans and Mice
|Gene||Gene Product||Mechanism of Obesity||In Human||In Rodent|
|Lep (ob)||Leptin, a fat-derived hormone||Mutation prevents leptin from delivering satiety signal; brain perceives starvation||Yes||Yes|
|LepR (db)||Leptin receptor||Same as above||Yes||Yes|
|POMC||Proopiomelanocortin, a precursor of several hormones and neuropeptides||Mutation prevents synthesis of melanocyte-stimulating hormone (MSH), a satiety signal||Yes||Yes|
|MC4R||Type 4 receptor for MSH||Mutation prevents reception of satiety signal from MSH||Yes||Yes|
|AgRP||Agouti-related peptide, a neuropeptide expressed in the hypothalamus||Overexpression inhibits signal through MC4R||No||Yes|
|PC-1||Prohormone convertase 1, a processing enzyme||Mutation prevents synthesis of neuropeptide, probably MSH||Yes||No|
|Fat||Carboxypeptidase E, a processing enzyme||Same as above||No||Yes|
|Tub||Tub, a hypothalamic protein of unknown function||Hypothalamic dysfunction||No||Yes|
|TrkB||TrkB, a neurotrophin receptor||Hyperphagia due to uncharacterized hypothalamic defect||Yes||Yes|
A central pathway through which leptin acts to regulate appetite and body weight. Leptin signals through proopiomelanocortin (POMC) neurons in the hypothalamus to induce increased production of α-melanocyte-stimulating hormone (α-MSH), requiring the processing enzyme PC-1 (proenzyme convertase 1). α-MSH acts as an agonist on melanocortin-4 receptors to inhibit appetite, and the neuropeptide AgRp (Agouti-related peptide) acts as an antagonist of this receptor. Mutations that cause obesity in humans are indicated by the solid green arrows.
In addition to these human obesity genes, studies in rodents reveal several other molecular candidates for hypothalamic mediators of human obesity or leanness. The tub gene encodes a hypothalamic peptide of unknown function; mutation of this gene causes late-onset obesity. The fat gene encodes carboxypeptidase E, a peptide-processing enzyme; mutation of this gene is thought to cause obesity by disrupting production of one or more neuropeptides. AgRP is coexpressed with NPY in arcuate nucleus neurons. AgRP antagonizes α-MSH action at MC4 receptors, and its overexpression induces obesity. In contrast, a mouse deficient in the peptide MCH, whose administration causes feeding, is lean.
A number of complex human syndromes with defined inheritance are associated with obesity (Table 77-2). Although specific genes have limited definition at present, their identification will likely enhance our understanding of more common forms of human obesity. In the Prader-Willi syndrome, a multigenic neurodevelopmental disorder, obesity coexists with short stature, mental retardation, hypogonadotropic hypogonadism, hypotonia, small hands and feet, fish-shaped mouth, and hyperphagia. Most patients have a deletion in the 15q11-13 chromosomal region, and reduced expression of the signaling protein necdin may be an important cause of defective hypothalamic neural development in this disorder (Chap. 62). Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by obesity, mental retardation, retinitis pigmentosa, diabetes, renal and cardiac malformations, polydactyly, and hypogonadotropic hypogonadism. At least 12 genetic loci have been identified, and most of the encoded proteins form two multiprotein complexes that are involved in ciliary function and microtubule-based intracellular transport. Recent evidence suggests that mutations might disrupt leptin receptor trafficking in key hypothalamic neurons, causing leptin resistance.
Table 77-2 A Comparison of Syndromes of Obesity—Hypogonadism and Mental Retardation |Favorite Table|Download (.pdf)
Table 77-2 A Comparison of Syndromes of Obesity—Hypogonadism and Mental Retardation
|Inheritance||Sporadic; two-thirds have defect||Autosomal recessive||Autosomal recessive||Probably autosomal recessive||Autosomal recessive|
|Stature||Short||Normal; infrequently short||Normal; infrequently short||Short or tall||Normal|
|Moderate to severe||Early onset, 1–2 years||Early onset, 2–5 years||Mid-childhood, age 5|
|Onset 1–3 years|
|Craniofacies||Narrow bifrontal diameter||Not distinctive||Not distinctive||High nasal bridge||Acrocephaly|
|Almond-shaped eyes||Arched palate||Flat nasal bridge|
|Strabismus||Open mouth||High-arched palate|
|V-shaped mouth||Short philtrum|
|Limbs||Small hands and feet||Polydactyly||No abnormalities||Hypotonia||Polydactyly|
|Hypotonia||Narrow hands and feet||Syndactyly|
|Reproductive status||1° Hypogonadism||1° Hypogonadism||Hypogonadism in males but not in females||Normal gonadal function or hypogonadotrophic hypogonadism||2° Hypogonadism|
|Other features||Enamel hypoplasia||Dysplastic ears|
|Mental retardation||Mild to moderate||Normal intelligence||Mild||Slight|
Although obese patients commonly have central obesity, hypertension, and glucose intolerance, they lack other specific stigmata of Cushing's syndrome (Chap. 342). Nonetheless, a potential diagnosis of Cushing's syndrome is often entertained. Cortisol production and urinary metabolites (17OH steroids) may be increased in simple obesity. Unlike in Cushing's syndrome, however, cortisol levels in blood and urine in the basal state and in response to corticotropin-releasing hormone (CRH) or ACTH are normal; the overnight 1-mg dexamethasone suppression test is normal in 90%, with the remainder being normal on a standard 2-day low-dose dexamethasone suppression test. Obesity may be associated with excessive local reactivation of cortisol in fat by 11β-hydroxysteroid dehydrogenase 1, an enzyme that converts inactive cortisone to cortisol.
The possibility of hypothyroidism should be considered, but it is an uncommon cause of obesity; hypothyroidism is easily ruled out by measuring thyroid-stimulating hormone (TSH). Much of the weight gain that occurs in hypothyroidism is due to myxedema (Chap. 341).
Patients with insulinoma often gain weight as a result of overeating to avoid hypoglycemic symptoms (Chap. 345). The increased substrate plus high insulin levels promote energy storage in fat. This can be marked in some individuals but is modest in most.
Craniopharyngioma and other disorders involving the hypothalamus
Whether through tumors, trauma, or inflammation, hypothalamic dysfunction of systems controlling satiety, hunger, and energy expenditure can cause varying degrees of obesity (Chap. 339). It is uncommon to identify a discrete anatomic basis for these disorders. Subtle hypothalamic dysfunction is probably a more common cause of obesity than can be documented using currently available imaging techniques. Growth hormone (GH), which exerts lipolytic activity, is diminished in obesity and is increased with weight loss. Despite low GH levels, insulin-like growth factor (IGF)-I (somatomedin) production is normal, suggesting that GH suppression is a compensatory response to increased nutritional supply.
Pathogenesis of common obesity
Obesity can result from increased energy intake, decreased energy expenditure, or a combination of the two. Thus, identifying the etiology of obesity should involve measurements of both parameters. However, it is difficult to perform direct and accurate measurements of energy intake in free-living individuals; and the obese, in particular, often underreport intake. Measurements of chronic energy expenditure are possible using doubly labeled water or metabolic chamber/rooms. In subjects at stable weight and body composition, energy intake equals expenditure. Consequently, these techniques allow assessment of energy intake in free-living individuals. The level of energy expenditure differs in established obesity, during periods of weight gain or loss, and in the pre- or postobese state. Studies that fail to take note of this phenomenon are not easily interpreted.
There is continued interest in the concept of a body weight "set point." This idea is supported by physiologic mechanisms centered around a sensing system in adipose tissue that reflects fat stores and a receptor, or "adipostat," that is in the hypothalamic centers. When fat stores are depleted, the adipostat signal is low, and the hypothalamus responds by stimulating hunger and decreasing energy expenditure to conserve energy. Conversely, when fat stores are abundant, the signal is increased, and the hypothalamus responds by decreasing hunger and increasing energy expenditure. The recent discovery of the ob gene, and its product leptin, and the db gene, whose product is the leptin receptor, provides important elements of a molecular basis for this physiologic concept (see above).
What is the status of food intake in obesity? (Do the obese eat more than the lean?)
This question has stimulated much debate, due in part to the methodologic difficulties inherent in determining food intake. Many obese individuals believe that they eat small quantities of food, and this claim has often been supported by the results of food intake questionnaires. However, it is now established that average energy expenditure increases as individuals get more obese, due primarily to the fact that metabolically active lean tissue mass increases with obesity. Given the laws of thermodynamics, the obese person must therefore eat more than the average lean person to maintain their increased weight. It may be the case, however, that a subset of individuals who are predisposed to obesity have the capacity to become obese initially without an absolute increase in caloric consumption.
What is the state of energy expenditure in obesity?
The average total daily energy expenditure is higher in obese than lean individuals when measured at stable weight. However, energy expenditure falls as weight is lost, due in part to loss of lean body mass and to decreased sympathetic nerve activity. When reduced to near-normal weight and maintained there for awhile, (some) obese individuals have lower energy expenditure than (some) lean individuals. There is also a tendency for those who will develop obesity as infants or children to have lower resting energy expenditure rates than those who remain lean.
The physiologic basis for variable rates of energy expenditure (at a given body weight and level of energy intake) is essentially unknown. A mutation in the human β3-adrenergic receptor may be associated with increased risk of obesity and/or insulin resistance in certain (but not all) populations.
One recently described component of thermogenesis, called nonexercise activity thermogenesis (NEAT), has been linked to obesity. It is the thermogenesis that accompanies physical activities other than volitional exercise such as the activities of daily living, fidgeting, spontaneous muscle contraction, and maintaining posture. NEAT accounts for about two-thirds of the increased daily energy expenditure induced by overfeeding. The wide variation in fat storage seen in overfed individuals is predicted by the degree to which NEAT is induced. The molecular basis for NEAT and its regulation is unknown.
Leptin in typical obesity
The vast majority of obese persons have increased leptin levels but do not have mutations of either leptin or its receptor. They appear, therefore, to have a form of functional "leptin resistance." Data suggesting that some individuals produce less leptin per unit fat mass than others or have a form of relative leptin deficiency that predisposes to obesity are at present contradictory and unsettled. The mechanism for leptin resistance, and whether it can be overcome by raising leptin levels or combining leptin with other treatments in a subset of obese individuals, is not yet established. Some data suggest that leptin may not effectively cross the blood-brain barrier as levels rise. It is also apparent from animal studies that leptin signaling inhibitors, such as SOCS3 and PTP1b, are involved in the leptin-resistant state.
Pathologic Consequences of Obesity
(See also Chap. 78) Obesity has major adverse effects on health. Obesity is associated with an increase in mortality, with a 50–100% increased risk of death from all causes compared to normal-weight individuals, mostly due to cardiovascular causes. Obesity and overweight together are the second leading cause of preventable death in the United States, accounting for 300,000 deaths per year. Mortality rates rise as obesity increases, particularly when obesity is associated with increased intraabdominal fat (see above). Life expectancy of a moderately obese individual could be shortened by 2–5 years, and a 20- to 30-year-old male with a BMI >45 may lose 13 years of life. It is also apparent that the degree to which obesity affects particular organ systems is influenced by susceptibility genes that vary in the population.
Insulin resistance and type 2 diabetes mellitus
Hyperinsulinemia and insulin resistance are pervasive features of obesity, increasing with weight gain and diminishing with weight loss (Chap. 242). Insulin resistance is more strongly linked to intraabdominal fat than to fat in other depots. Molecular links between obesity and insulin resistance in fat, muscle, and liver have been sought for many years. Major factors include: (1) insulin itself, by inducing receptor downregulation; (2) free fatty acids that are increased and capable of impairing insulin action; (3) intracellular lipid accumulation; and (4) several circulating peptides produced by adipocytes, including the cytokinesTNF-α and IL-6, RBP4, and the "adipokines" adiponectin and resistin that have altered expression in obese adipocytes, and can modify insulin action. Additional mechanisms are obesity-linked inflammation, including infiltration of macrophages into tissues including fat, and induction of the endoplasmic reticulum stress response, that can bring about resistance to insulin action in cells. Despite the prevalence of insulin resistance, most obese individuals do not develop diabetes, suggesting that diabetes requires an interaction between obesity-induced insulin resistance and other factors such as impaired insulin secretion (Chap. 344). Obesity, however, is a major risk factor for diabetes, and as many as 80% of patients with type 2 diabetes mellitus are obese. Weight loss and exercise, even of modest degree, increase insulin sensitivity and often improve glucose control in diabetes.
Disorders that affect the reproductive axis are associated with obesity in both men and women. Male hypogonadism is associated with increased adipose tissue, often distributed in a pattern more typical of females. In men whose weight is >160% ideal body weight (IBW), plasma testosterone and sex hormone–binding globulin (SHBG) are often reduced, and estrogen levels (derived from conversion of adrenal androgens in adipose tissue) are increased (Chap. 346). Gynecomastia may be seen. However, masculinization, libido, potency, and spermatogenesis are preserved in most of these individuals. Free testosterone may be decreased in morbidly obese men whose weight is >200% IBW.
Obesity has long been associated with menstrual abnormalities in women, particularly in women with upper body obesity (Chap. 347). Common findings are increased androgen production, decreased SHBG, and increased peripheral conversion of androgen to estrogen. Most obese women with oligomenorrhea have the polycystic ovarian syndrome (PCOS), with its associated anovulation and ovarian hyperandrogenism; 40% of women with PCOS are obese. Most nonobese women with PCOS are also insulin-resistant, suggesting that insulin resistance, hyperinsulinemia, or the combination of the two are causative or contribute to the ovarian pathophysiology in PCOS in both obese and lean individuals. In obese women with PCOS, weight loss or treatment with insulin-sensitizing drugs often restores normal menses. The increased conversion of androstenedione to estrogen, which occurs to a greater degree in women with lower body obesity, may contribute to the increased incidence of uterine cancer in postmenopausal women with obesity.
The Framingham Study revealed that obesity was an independent risk factor for the 26-year incidence of cardiovascular disease in men and women [including coronary disease, stroke, and congestive heart failure (CHF)]. The waist-to-hip ratio may be the best predictor of these risks. When the additional effects of hypertension and glucose intolerance associated with obesity are included, the adverse impact of obesity is even more evident. The effect of obesity on cardiovascular mortality in women may be seen at BMIs as low as 25. Obesity, especially abdominal obesity, is associated with an atherogenic lipid profile; with increased low-density lipoprotein cholesterol, very low density lipoprotein, and triglyceride; and with decreased high density lipoprotein cholesterol and decreased levels of the vascular protective adipokine adiponectin (Chap. 356). Obesity is also associated with hypertension. Measurement of blood pressure in the obese requires use of a larger cuff size to avoid artifactual increases. Obesity-induced hypertension is associated with increased peripheral resistance and cardiac output, increased sympathetic nervous system tone, increased salt sensitivity, and insulin-mediated salt retention; it is often responsive to modest weight loss.
Obesity may be associated with a number of pulmonary abnormalities. These include reduced chest wall compliance, increased work of breathing, increased minute ventilation due to increased metabolic rate, and decreased functional residual capacity and expiratory reserve volume (Chap. 252). Severe obesity may be associated with obstructive sleep apnea and the "obesity hypoventilation syndrome" with attenuated hypoxic and hypercapnic ventilatory responses (Chap. 264). Sleep apnea can be obstructive (most common), central, or mixed and is associated with hypertension. Weight loss (10–20 kg) can bring substantial improvement, as can major weight loss following gastric bypass or restrictive surgery. Continuous positive airway pressure has been used with some success.
Obesity is frequently associated with the common disorder nonalcoholic fatty liver disease (NAFLD). This hepatic fatty infiltration of NAFLD can progress in a subset to inflammatory nonalcoholic steatohepatitis (NASH) and more rarely to cirrhosis and hepatocellular carcinoma. Steatosis has been noted to improve following weight loss, secondary to diet or bariatric surgery. The mechanism for the association remains unclear. Obesity is associated with enhanced biliary secretion of cholesterol, supersaturation of bile, and a higher incidence of gallstones, particularly cholesterol gallstones (Chap. 311). A person 50% above IBW has about a sixfold increased incidence of symptomatic gallstones. Paradoxically, fasting increases supersaturation of bile by decreasing the phospholipid component. Fasting-induced cholecystitis is a complication of extreme diets.
Obesity in males is associated with higher mortality from cancer, including cancer of the esophagus, colon, rectum, pancreas, liver, and prostate; obesity in females is associated with higher mortality from cancer of the gallbladder, bile ducts, breasts, endometrium, cervix, and ovaries. Some of the latter may be due to increased rates of conversion of androstenedione to estrone in adipose tissue of obese individuals. Other possible mechanistic links are other hormones whose levels are linked to nutritional state, including insulin, leptin, adiponectin, and IGF-1. It has been estimated that obesity accounts for 14% of cancer deaths in men and 20% in women in the United States.
Bone, joint, and cutaneous disease
Obesity is associated with an increased risk of osteoarthritis, no doubt partly due to the trauma of added weight bearing, but potentially linked as well to activation of inflammatory pathways that could promote synovial pathology. The prevalence of gout may also be increased (Chap. 333). Among the skin problems associated with obesity is acanthosis nigricans, manifested by darkening and thickening of the skinfolds on the neck, elbows, and dorsal interphalangeal spaces. Acanthosis reflects the severity of underlying insulin resistance and diminishes with weight loss. Friability of skin may be increased, especially in skinfolds, enhancing the risk of fungal and yeast infections. Finally, venous stasis is increased in the obese.