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The Disease of Obesity
Fat Is a Stubborn Foe, Columbia's Leibel Reports

By Rich McManus

Nothing seems to love the human body like fat, arriving oftentimes unbidden, and remaining snuggled up close until substantial means — including regular exercise, diet, drugs, or even surgery — are employed to thwart its lusty embrace.

Something about the human body just wants to be fat, gravitates toward lushness of flesh, and it is investigators such as Columbia University's Dr. Rudolph Leibel — who spoke at the Clinical Center's Contemporary Clinical Medicine: Great Teachers segment of Grand Rounds on Jan. 14 — who are discovering the genetic and hormonal elements that feed the body's hunger for adiposity.Lipsett Amphitheater swelled to standing-room-only proportion for Leibel's presentation, "Obesity: A Disease, Not a Character Flaw," reflecting medical interest in the booming rates of booming beltlines in the United States.

"There has been an enormous increase in the prevalence of obesity in the U.S.," said Leibel, showing epidemiologic maps indicating steady weight gain in the past dozen or so years; Alabama appears to be the heaviest state at the moment. The rise in American obesity is paralleled by rising diagnoses of diabetes, not to mention a host of other illnesses, including hypertension. "Obesity results in lots of suffering, and lots of cost," Leibel noted. "About 5 to 7 percent of the total U.S. health budget is accounted for by obesity-related ailments."

Speaking from an evolutionary perspective about environmental, and by selection, genetic tendencies for holding weight up or down, Leibel noted two up-regulating factors for fat mass: reproductive requirements, and protection against environmental vicissitudes, such as famine. Opposing fat acquisition (in addition to glancing in the mirror) is at least one major factor — predator evasion. Or as Leibel explained, "You can't run away from your enemy if you're excessively overweight."

Fat mass is regulated chiefly by signals mediated through the hypothalamus (a pea-sized structure above the pituitary gland), Leibel said. In the short term, incoming signals are mainly metabolites; in the intermediate term, gut hormones such as ghrelin released from the stomach exert their effect; and in the long-term, adipocytes, or fat cells, send signals such as leptin, a substance that, when available in adequate supply, pushes you away from the table and, when in short supply, draws you back to the buffet. The net evolutionary sense of these systems appears to be this: defense against the loss of fat is much greater than defense against gain of fat.

"Obesity is a game of inches, like baseball," Leibel said. "Small differences add up, particularly over a long period." For example, a mere 3.6 percent excess in intake of calories versus output can account for the 30-35-pound weight gain most adults experience between ages 25 and 55 years.

Ranging away from the belly to the brain, Leibel stated, without irony, that "the guts of the (fat-determining) system is in the hypothalamus." The arcuate nucleus, or "nose" of the hypothalamus, is the seat of first- and second-messenger molecular action determining fat intake. Evidence in animal studies shows that when specific neurons in specific regions of the hypothalamus are either ablated or preserved, researchers can "adjust" for fat or thin rodents. Leibel described a sort of biological tango wherein orexigenic factors battle anorexigenic factors to maintain homeostatic balance in the body. Partners in the dance include leptin and its receptors, neuropeptides Y, POMC (proopiomelanocortin) genes and a host of neuropeptides. It is likely that all of the molecular players have not been discovered. Causes of human obesity range from monogenic — as in mutations in the MC4R gene, which represents the most common form of human obesity syndrome (accounting for some 3-5 percent of severe obesity in children) — to polygenic. The genetic basis for most human obesity has not yet been identified. It is likely that the interaction of several genes, each with modest effects, determines one's predisposition to obesity, Leibel said.

He reported that the heritability of obesity, which is in the range of 65-70 percent, is much higher than in many other diseases. He guessed that some 30-40 genes play a role in the control of energy homeostasis. "The trick is, how do they play with one another, and with the environment, to produce the phenotype (obesity)?"

Pausing for some anthropological observations, Leibel noted that the modern environment — studded with cell phones and dotted with restaurants that provide take-out — is not well tuned to man's genetic makeup, forged as it was in hunter/gatherer days. "An organism designed in one environment (prehistory) now finds itself in the modern world...This helps explain why obesity is so hard to treat: We're just not designed to be skinny organisms in this environment."

Most current treatments for obesity don't work, Leibel said, because they are bucking such powerful biological defense systems. But that's no reason to toss out the Adidas, for "even a little bit of weight loss can do a lot of good — modest weight loss improves health." He urged, "Use whatever works, but is healthy. Try different approaches." He cautioned that diet composition is "not a major player" in weight control because "a calorie is a calorie, no matter where it comes from."

He mentioned two drugs licensed for weight loss, sibutramine and orlistat; the latter blocks absorption of fat, but can have unpleasant "social consequences" as users may have to take frequent bathroom trips. He called bariatric surgery a "draconian" approach, but allowed that it is the most effective intervention, especially the procedure known as gastric bypass roux-en-y.

Peering into the future of body mass reduction, Leibel said there is a great need for new molecular targets, especially gut-related signals, and called for reduced consumption of calorie-dense foods. He also repeated the prescription that nobody wants to hear, especially when it's 15 degrees outside — a need for increased exercise.

To view Leibel's talk in its entirety, visit http://videocast.nih.gov.


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