Students and parents packed Wright Lecture Hall on Saturday, eager to hear scientist  Dr. D. Scott Weigle, MD, speak on the current medical and societal phenomenon of obesity. Mitigation of this nationwide problem requires a fundamental understanding: What exactly is going on inside the body of an obese person?

Weigle began his talk, “Body Weight Regulation and Obesity: From Mouse to Man,” by discussing the body’s normal system of weight management. The body has feedback systems designed to maintain body weight, and when this system breaks down, one gains or loses weight.

In order to maintain body weight, energy output (metabolism) is regulated to match energy input (feeding).  When energy, stored as fat or circulating in the blood as glucose, is low, the body responds by decreasing its metabolic rate, or energy expenditure, and providing the hunger sensations to motivate feeding.  When energy stores are high, the body responds by increasing its energy expenditures and replacing the sensation of hunger with that of fullness. We are all familiar with these sensations of hunger and satiation.  But how does the body regulate them?

Weigle explained that the body has ways of sensing the levels of its fuel reserves. Fat cells produce hormone signals, which travel through the circulatory system to the brain.  These signals also fluctuate in response to recent food consumption. The brain takes the levels of these signals as indicators of the body’s energy stores and responds by sending out neuronal signals to either increase or decrease the amount we eat in order to maintain energy stores and weight. 

What are these signals?  In 1994, in the lab of Jeffrey Friedman at the Rockefeller University in New York City, leptin (from Greek leptos for “slender”) was identified as the protein hormone that informs the brain of the body’s energy reserves.  The gene encoding leptin in mice had already been studied for many years at the Jackson Laboratory – a mouse genetics lab in Maine – as a genetically heritable factor that resulted in obesity, and the same scientists had also shown that the factor was transmissible through the blood.  But it was not until ’94 that the identity, chromosomal location and DNA sequence of the leptin gene were determined.  (The amount that was known about the factor now called leptin, even before the structure of DNA had been elucidated in 1953, is a testament to the power of classical genetics.)

Leptin is secreted by fat cells and travels through the blood to the brain where it affects the activity of neurons in control of appetite and metabolism, located in the hypothalamus (the region of the brain in control of many involuntary activities of the autonomic nervous system). When leptin levels are high, the hypothalamus sends signals to reduce feeding behavior (energy input) and increase metabolic rate (energy output). When leptin levels are low, the hypothalamus sends out signals to decrease metabolic rate and promote feeding. 

So leptin deficiency can cause obesity in mice.  But does it cause obesity in humans?   The answer is, in most cases, no. Leptin deficiency is a very severe condition and results in infertility in addition to obesity. Since people with two copies of the mutant leptin gene are infertile and cannot pass their genes on, natural selection works to eliminate this gene from the pool. Obese people and obese mice (in most cases) have very high levels of leptin, produced by their abundant fat cells.  Obesity is rarely a question of leptin deficiency.

Weigle suggested that the deficiency in obese subjects was, more often, the inability to respond to leptin signaling. For some reason, some obese mice, though they can produce leptin, lose the ability to respond to the hormone so that they continue to eat past the time when, normally, leptin signaling would have made them stop, gaining weight as a result. 

The mechanisms of resistance are not yet understood, but there is some evidence, from studies done in the mouse, that exercise increases leptin sensitivity while a high-fat diet decreases leptin sensitivity. Weigle suggested that these results about the effects of diet and exercise on leptin sensitivity in mice might explain the effectiveness of human weight-loss programs that emphasize exercise and a lower-fat diet.   

Much remains to be discovered about the mechanisms of leptin resistance and the causes of obesity, but no worries — researchers like Dr. Weigle are on the case.