Box 9-1. 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—a-melanocyte-stimulating

hormone (a-MSH) and cocaine and amphetamine-related transcript (CART). Both of these peptides are products of proopiomelanocortin (POMC). When the POMC/CART neurons are

activated by leptin signals, they exert catabolic effects mainly through the secretion of a-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 a-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.

a-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 b3 -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.

TABLE 9-26-- Medical Complications Associated with Obesity

Gastrointestinal Gallstones, pancreatitis, abdominal hernia, NAFLD (steatosis, steatohepatitis, and cirrhosis), and possibly GERD

Endocrine/metabolic Metabolic syndrome, insulin resistance, impaired glucose tolerance, type II diabetes mellitus, dyslipidemia, polycystic ovary syndrome

Cardiovascular Hypertension, coronary artery disease, congestive heart failure, arrhythmias, pulmonary hypertension, ischemic stroke, venous stasis, deep vein

thrombosis, pulmonary embolus

Respiratory Abnormal pulmonary function, obstructive sleep apnea, obesity hypoventilation syndrome

Musculoskeletal Osteoarthritis, gout, low back pain

Gynecologic Abnormal menses, infertility

Genitourinary Urinary stress incontinence

Ophthalmologic Cataracts

Neurologic Idiopathic intracranial hypertension (pseudotumor cerebri)

Cancer Esophagus, colon, gallbladder, prostate, breast, uterus, cervix, kidney

Postoperative events Atelectasis, pneumonia, deep vein thrombosis, pulmonary embolus

Data from Klein S, Wadden T, Sugerman HJ: AGA technical review on obesity. Gastroenterol 123:882, 2002. NAFLD, non-alcoholic fatty liver disease; GERD, gastroesophageal reflux

disease.

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 socalled

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.[79]

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.

Date: 2016-04-22; view: 839