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Monday 19 April 2004

Obesity is associated with many adverse health effects, including an increased risk of diabetes and heart disease.

The combined condition of obesity, diabetes and heart disease is sometimes referred to as the metabolic syndrome.

One of the factors that best correlates obesity with the rest of the metabolic syndrome is not overall body mass, but the distribution of adipose tissue in the abdominal region, visceral obesity.

Obesity is a global epidemic resulting from sedentary lifestyles, improved socioeconomic conditions, and availability of processed, high calorie foods and soft drinks in industrialized societies. Approximately 35% of the US adult population is overweight, and an additional 30% of adults are obese; the prevalence of obesity in children and adolescents is also increasing; indeed, reaching epidemic proportions.78 Because obesity is correlated with increased morbidity and mortality, it is important to define and recognize it, to understand its causes, and to be able to initiate appropriate measures to prevent or manage it. Behavioral and dietary changes are the initial therapeutic strategies; weight-loss drugs should be used with caution, especially herbal preparations that combine ephedra alkaloids and caffeine, because there are serious potential adverse reactions.

How does one measure fat accumulation? There are several highly technical ways to approximate the measurement, but for practical considerations, the following ones are commonly used:
Some expression of weight in relation to height, especially the measurement referred to as the body mass index (BMI)
Skin fold measurements

Various body circumferences, particularly the ratio of the waist to hip circumference.

The BMI, expressed in kilograms per square meter, is closely correlated with body fat. A BMI of approximately 25 kg/m2 is considered normal. Individuals with BMI ≥30 kg/m2 are considered obese, and those whose BMI falls between 25.0 to 29.9 kg/m2 are considered overweight79 (Table 9-25). As noted, the prevalence of obesity-related diseases, such as diabetes, hypertension, and coronary artery disease, begins to increase at BMI values >25.0 kg/m2 and then continues the ascent at higher values.

The untoward effects of obesity are related not only to the total body weight, but also to the distribution of the stored fat. Central or visceral obesity, in which fat accumulates in the trunk and in the abdominal cavity (in the mesentery and around viscera), is associated with a much higher risk for several diseases than is excess accumulation of fat diffusely in subcutaneous tissue.

The etiology of obesity is complex and incompletely understood. Involved are genetic, environmental, and psychological factors. However, simply put, obesity is a disorder of energy balance. When food-derived energy chronically exceeds energy expenditure, the excess calories are stored as triglycerides in adipose tissue. The two sides of the energy equation, intake and expenditure, are finely regulated by neural and hormonal mechanisms.


In most individuals, when food intake increases, so does the consumption of calories, and vice versa. Hence, body weight is maintained within a narrow range for many years.

Apparently, this fine balance is maintained by an internal set point, or "lipostat," that can sense the quantity of the energy stores (adipose tissue) and appropriately regulate the food intake as well as the energy expenditure. The molecular nature of the lipostat remained obscure for many years, but with the identification of leptin in 1994, a series of breathtaking discoveries changed the picture.

There are three components of this system:
- The afferent system, which generates humoral signals from the adipose tissue (leptin), pancreas (insulin), and stomach (ghrelin)
- The central processing unit, located primarily in the hypothalamus, which integrates the afferent signals
- The effector system, which carries out "orders" from the hypothalamic nuclei in the form of feeding behavior and energy expenditure.

Energy expenditure occurs through a variety of hormonal (e.g., thyrotropin-releasing hormone) and autonomic intermediaries.

Among the afferent signals, insulin and leptin exert long-term control over the energy cycle by activating catabolic circuits and inhibiting anabolic pathways, as discussed in greater detail below. By contrast, ghrelin is predominately a short-term mediator. Produced in the stomach, ghrelin levels rise sharply before every meal and fall promptly when the stomach is "filled." In fact, it is thought that the success of gastric bypass surgery in massively obese individuals may relate more to the associated suppression of ghrelin levels than to an anatomic reduction in stomach capacity.

Whereas both insulin and leptin influence the energy cycle, available data suggest that leptin has a more important role than insulin in the central nervous system control of energy homeostasis.81 Hence, our discussion will be focused on leptin, recognizing that leptin and insulin share some of their actions.

It is now established that adipocytes communicate with the hypothalamic centers that control appetite and energy expenditure by secreting leptin, a member of the cytokine family. When there is an abundance of stored energy in the form of adipose tissue, the resultant high levels of leptin cross the blood-brain barrier, binding to leptin receptors. Leptin receptor signaling has two effects: it inhibits anabolic circuits that normally promote food intake and inhibit energy expenditure, and, through a distinct set of neurons, leptin triggers catabolic circuits.

The net effect of leptin, therefore, is to reduce food intake and promote energy expenditure. Hence, over a period of time, energy stores (adipocytes) are reduced, and weight is lost. This in turn reduces the circulating levels of leptin, and a new equilibrium is reached. This cycle is reversed when adipose tissue is lost and leptin levels are reduced below a threshold. Equilibrium is again reached, since with low leptin levels, the anabolic circuits are relieved of inhibition and catabolic circuits are not activated, resulting in net gain of weight.

The molecular basis of leptin action is extremely complex and not yet fully unraveled. For the most part, leptin exerts its function through a series of integrated neural pathways referred to as the leptin-melanocortin circuit, described in Box 9-1 and illustrated in Figure 9-33. The understanding of this circuitry is important since obesity is a serious public health problem, and development of antiobesity drugs will depend on a full understanding of these pathways.


Obesity, particularly central obesity, increases the risk for a number of conditions, including diabetes, hypertension, osteoarthritis, pancreatitis, and many others. Only some of these complications are discussed here. The mechanisms underlying these associations are complex and likely to be interrelated.

Obesity, for instance, is associated with insulin resistance and hyperinsulinemia, important features of non-insulin-dependent, or type II, diabetes, and weight loss is associated with improvement. It has been speculated that excess insulin, in turn, may play a role in the retention of sodium, expansion of blood volume, production of excess norepinephrine, and smooth muscle proliferation that are the hallmarks of hypertension. Regardless of whether these pathogenic mechanisms are actually operative, the risk of developing hypertension among previously normotensive persons increases proportionately with weight.

Obesity is also associated with a somewhat distinctive metabolic syndrome, the so-called syndrome X, which is characterized by abdominal obesity, insulin resistance, hypertriglyceridemia, low serum HDL, hypertension, and increased risk for coronary artery disease.82

Obese persons are likely to have hypertriglyceridemia and a low HDL cholesterol value, and these factors may increase the risk of coronary artery disease. The association between obesity and heart disease is not straightforward, and the linkage may be related to the associated diabetes and hypertension rather than to weight. Nevertheless, the American Heart Association has recently added obesity to its list of major risk factors.

Nonalcoholic steatohepatitis occurs in adolescents and adults who are obese and have type II diabetes. Fatty change accompanied by liver cell injury and inflammation may progress to fibrosis or regress following weight loss.

Cholelithiasis (gallstones) is six times more common in obese than in lean subjects. The mechanism is mainly an increase in total body cholesterol, increased cholesterol turnover, and augmented biliary excretion of cholesterol in the bile, which in turn predisposes to the formation of cholesterol-rich gallstones (Chapter 18).

Hypoventilation syndrome is a constellation of respiratory abnormalities in very obese persons. It has been called the pickwickian syndrome, after the fat lad who was constantly falling asleep in Charles Dickens’ Pickwick Papers. Hypersomnolence, both at night and during the day, is characteristic and is often associated with apneic pauses during sleep, polycythemia, and eventual right-sided heart failure.

Marked adiposity predisposes to the development of degenerative joint disease (osteoarthritis). This form of arthritis, which typically appears in older persons, is attributed in large part to the cumulative effects of wear and tear on joints. It is reasonable to assume that the greater the body burden of fat, the greater the trauma to joints with passage of time.

Obesity increases the risk of ischemic stroke in both men and women. Abdominal obesity is associated with increased risk of venous thrombosis.

Somewhat controversial is the association between obesity and cancer. A recent large prospective study has revealed an association between increasing BMI and mortality from many forms of cancer, including cancers of the esophagus, colon, rectum, liver, and non-Hodgkin lymphoma.84 The basis of this association is difficult to discern.

With hormone-dependent cancers, such as those arising in the endometrium, the blame can be placed on hormonal imbalance since obesity is known to raise estrogen levels, but for others we remain in the dark.


Glucocorticoids have been associated as a risk factor for the metabolic syndrome, but most obese individuals have normal levels of circulating corticosteroids.

Active corticosteroids such as cortisol and corticosterone activate the glucocorticoid receptor, a nuclear hormone receptor and transcription factor.

Obese individuals have elevated levels in adipose tissue of a key enzyme in glucocorticoid metabolism, 11beta hydroxysteroid dehydrogenase type 1 (11betaHSD-1). 11betaHSD-1 interconverts inactive corticosteroids and the active form.

When present in cells, 11betaHSD-1 can convert inactive corticosteroids from the blood to create locally high concentrations in a tissue such as adipose tissue.

When activated in adipose tissue, GR increases the level of visceral fat, induces insulin resistance and dyslipidemias that increase the risk of heart disease.

The mechanisms by which GR might induce the various aspects of the metabolic syndrome are a key area of research. One of the genes activated by GR is lipoprotein lipase.

When GR is activated in visceral adipose tissue, it will increase the expression of lipoprotein lipase (LPL). This enzyme hydrolyzes triglycerides in plasma, releasing free fatty acids into tissues, where they can be reassembled into triglycerides.

In visceral adipose, this GR-driven overexpression of lipoprotein lipase will result in the increased deposits of visceral fat that are observed. Genes thought to be involved in insulin resistance also appear to be affected by altered 11betaHSD-1 corticosteroid metabolism in visceral fat.

This includes downregulation of resistin and adipoQ, and induction of TNF-alpha. The elevated free fatty acids and active corticosteroids released from visceral fat may account for the metabolic changes in liver associated with the metabolic syndrome.

Antidiabetic thiazoidinedione drugs such as troglitazone and Avandia act as agonists of another nuclear receptor, PPAR-gamma. These drugs activate PPAR-gamma and repress expression of 11betaHSD-1 in visceral tissue, perhaps accounting in part for the antidiabetic insulin sensitizing properties of these drugs.

Genetics of obesity

Obesity is a disorder with a multifactorial etiology. Only rarely does it result from single gene disorders. Evidence supporting an important role for genes in weight control includes familial clustering of obesity and higher concordance of body mass index (BMI) among monozygotic twins (74%) versus dizygotic twins (32%) living in the same environment. Although monogenic forms of obesity in humans are rare, studies of these genetic forms of obesity and their murine counterparts have significantly advanced our understanding of the molecular basis of obesity. Some of these are discussed below.

In recent years many "obesity" genes have been identified. As might be expected, they encode the molecular components of the neuroendocrine system that regulates energy balance. Leptin, the key player in energy homeostasis, is the product of the OB gene. Its role as an antiobesity factor is buttressed by the observation that mice homozygous for mutations in the leptin gene (OB/OB) do not secrete leptin, are massively obese, and are "cured" by the administration of exogenous leptin. Mice with mutations in the leptin receptor (db/db) are also obese, but, unlike the case with ob/ob mice, their obesity cannot be ameliorated by the administration of leptin. In these mice, obesity occurs because the leptin-mediated afferent signals impinging on the hypothalamus fail to regulate appetite and energy expenditure.

Although leptin receptors are expressed at several sites in the brain, those most critical for regulation of the leptin- melanocortin circuit are expressed in the arcuate nucleus of the hypothalamus. There are two major types of neurons in this locale that bear leptin receptors: one set (oraxogenic) produces appetite-stimulating neurotransmitters called neuropeptide Y (NPY) and agouti-related peptide (AgRP). These are appropriately called NPY/AgRP neurons (see Fig. 9-33). As can be surmised from the discussion in the text, leptin reduces the expression of NPY and AgRP. The other set of leptin-sensitive neurons, the so-called POMC/CART neurons, transcribe two anorexigenic neuropeptides-α-melanocyte-stimulating hormone (α-MSH) and cocaine and amphetamine-related transcript (CART). Both of these peptides are products of pro-opiomelanocortin (POMC). When the POMC/CART neurons are activated by leptin signals, they exert catabolic effects mainly through the secretion of α-MSH. As indicated in Figure 9-33, the NPY/AgRP and POMC/CART neurons are referred to as first-order neurons of the leptin-melanocortin circuit, since they are the initial targets of leptin action. The neurotransmitters produced by them (NPY, AgRP, and α-MSH) then interact through their own specific receptors with second-order neurons that trigger the efferent systems with peripheral actions. The effects of these neurotransmitters are described next.

In the anabolic pathway, the first-order NPY/AgRP neurons make monosynaptic connections to second-order neurons, which express oraxogenic peptides melanin-concentrating hormone (MCH) and oraxins A and B. As illustrated in Figure 9-33, NPY released from first-order neurons binds to its receptor on second-order neurons and thus transmits feeding signals. Such signals are attenuated when leptin is in excess and are activated by low levels of leptin. AgRP, like NPY, exerts anabolic effects but by a somewhat distinct mechanism.

α-MSH produced by the POMC/CART neurons exerts its catabolic effects by binding to a set of second-order neurons (in the paraventricular nucleus) that express the melanocortin 4 receptor (MC4R). Catabolic output from the MC4R neurons is relayed to the periphery via the endocrine and autonomic systems. This reduces feeding and increases energy expenditure. The energy-consuming actions of MC4R neurons are mediated in part by the release of thyrotropin-releasing hormone (TRH), which activates the thyroxine axis through the anterior pituitary; TRH not only increases thermogenesis via secretion of thyroxine, but it is also an appetite suppressant. Corticotropin-releasing hormone (CRH) is another product of MC4R neurons. It induces anorexia and also activates the sympathetic nervous system. A subset of MC4R neurons projects to sympathetic motor output areas. Fibers from these areas innervate brown adipose tissue, rich in β3-adrenergic receptors. When these receptors are stimulated, they cause fatty acid hydrolysis and also uncouple energy production from storage. Thus, the fats are literally burned, and energy so produced is dissipated as heat.

It is noteworthy that each of the six single gene defects that give rise to human obesity involves proteins in the leptin- melanocortin pathway. Four of these are autosomal recessive and affect the leptin receptor, POMC, and PC1. (The last mentioned is a prohormone convertase that cleaves POMC). In all these cases, there is profound hyperphagia and childhood-onset massive obesity. While these four forms of genetic obesity are quite rare, those caused by mutations in the melanocortin receptor MC4R are by comparison quite common. In a recent study, 5% to 8% of a cohort of 500 obese individuals had functionally important mutations in the MC4R gene.83 In these patients, despite abundant fat stores and leptin, energy consumption cannot be stimulated. The sixth monogenic form of human obesity results from mutation in a transcription factor (SIM1) that is essential for the formation of second-order leptin neurons.

Despite the remarkable advances in our understanding of genetic control of pathways that regulate energy balance, the genetic basis of the most common forms of human obesity remains mysterious. As a multifactorial disorder, one might expect mutations or polymorphisms in several genes of small effect that give rise to obesity in concert with environmental factors. It is interesting to note that blood leptin levels are elevated in most humans with obesity. Clearly, the high levels of leptin are unable to down-regulate the anabolic pathways or activate the catabolic pathways. The basis of such leptin resistance is unclear but it may be contributed to by a decrease in the ability of leptin to cross the blood-brain barrier, possibly due to defective transport across endothelial cells. The fact that in some obese individuals leptin levels in the cerebrospinal fluid are lower than in the plasma supports this hypothesis.

Predisposition loci

- 10p12
- 12q24
- 13q32

See also

- overweight


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