Chapter 074. Biology of Obesity (Part 7)

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 a while, (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...
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Chapter 074. Biology of Obesity (Part 7) Chapter 074. Biology of Obesity (Part 7) WHAT IS THE STATE OF ENERGY EXPENDITURE INOBESITY? The average total daily energy expenditure is higher in obese than leanindividuals when measured at stable weight. However, energy expenditure falls asweight is lost, due in part to loss of lean body mass and to decreased sympatheticnerve activity. When reduced to near-normal weight and maintained there for awhile, (some) obese individuals have lower energy expenditure than (some) leanindividuals. There is also a tendency for those who will develop obesity as infantsor children to have lower resting energy expenditure rates than those who remainlean. The physiologic basis for variable rates of energy expenditure (at a givenbody weight and level of energy intake) is essentially unknown. A mutation in thehuman β3-adrenergic receptor may be associated with increased risk of obesityand/or insulin resistance in certain (but not all) populations. Homologues of theBAT uncoupling protein, named UCP-2 and UCP-3, have been identified in bothrodents and humans. UCP-2 is expressed widely, whereas UCP-3 is primarilyexpressed in skeletal muscle. These proteins may play a role in disordered energybalance. One newly described component of thermogenesis, called nonexerciseactivity thermogenesis (NEAT), has been linked to obesity. It is the thermogenesisthat accompanies physical activities other than volitional exercise, such as theactivities of daily living, fidgeting, spontaneous muscle contraction, andmaintaining posture. NEAT accounts for about two-thirds of the increased dailyenergy expenditure induced by overfeeding. The wide variation in fat storage seenin overfed individuals is predicted by the degree to which NEAT is induced. Themolecular basis for NEAT and its regulation is unknown. LEPTIN IN TYPICAL OBESITY The vast majority of obese persons have increased leptin levels but do nothave mutations of either leptin or its receptor. They appear, therefore, to have aform of functional leptin resistance. Data suggesting that some individualsproduce less leptin per unit fat mass than others or have a form of relative leptindeficiency that predisposes to obesity are at present contradictory and unsettled.The mechanism for leptin resistance, and whether it can be overcome by raisingleptin levels, is not yet established. Some data suggest that leptin may noteffectively cross the blood-brain barrier as levels rise. It is also apparent fromanimal studies that leptin signaling inhibitors, such as SOCS3 and PTP1b, areinvolved in the leptin-resistant state. Pathologic Consequences of Obesity (See also Chap. 75) Obesity has major adverse effects on health. Obesity isassociated with an increase in mortality, with a 50–100% increased risk of deathfrom all causes compared to normal-weight individuals, mostly due tocardiovascular causes. Obesity and overweight together are the second leadingcause of preventable death in the United States, accounting for 300,000 deaths peryear. Mortality rates rise as obesity increases, particularly when obesity isassociated with increased intraabdominal fat (see above). Life expectancy of amoderately 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 thatthe degree to which obesity affects particular organ systems is influenced bysusceptibility 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. 236). Insulinresistance is more strongly linked to intraabdominal fat than to fat in other depots.The molecular link between obesity and insulin resistance in tissues such as fat,muscle, and liver has been sought for many years. Major factors underinvestigation include: (1) insulin itself, by inducing receptor downregulation; (2)free fatty acids, known to be increased and capable of impairing insulin action; (3)intracellular lipid accumulation; and (4) various circulating peptides produced byadipocytes, including the cytokines TNF-α and IL-6, RBP4, and the adipokinesadiponectin and resistin, which are produced by adipocytes, have alteredexpression in obese adipocytes, and are capable of modifying insulin action.Despite nearly universal insulin resistance, most obese individuals do not developdiabetes, suggesting that the onset of diabetes requires an interaction betweenobesity-induced insulin resistance and other factors that predispose to diabetes,such as impaired insulin secretion (Chap. 338). Obesity, however, is a major riskfactor for diabetes, and as many as 80% of patients with type 2 diabetes mellitusare obese. Weight loss and exercise, even of modest degree, are associated withincreased insulin sensitivity and often improve glucose control in diabetes.