New Model Explains Regulation of Body Weight

BOSTON—A new mathematical model of the physiological regulation of body weight suggests a potential mechanism underlying the difficulty of losing weight, one that includes aspects of two competing hypotheses of weight regulation.

In the January issue of Cell Metabolism, Massachusetts General Hospital (MGH) investigators outline a system in which there may be several steady states to which an animal's weight tends to gravitate, rather than a single "set point."

"There are problems with both of the current hypotheses for how the body balances energy intake and expenditure to maintain a stable weight," said Joshua Tam, a doctoral student working in the Steele Laboratory in the MGH Department of Radiation Oncology and lead author of the study. "While our model has its own limitations, if it holds up, it may help us better understand the body's system for weight regulation."

The well-known tendency for body weight to remain stable in spite of changes in diet or energy expenditure led to the development of the "set-point" hypothesis, which holds that an individual's metabolism acts to oppose changes to a physiologically predetermined body weight. Opponents of the theory argue that a natural set-point would prevent the development of obesity and the body's weight "settling point" is determined solely by environmental factors, such as the availability of food, along with physical activity and other behavioral factors.

Opposing the settling point theory are study results showing that if given access only to low-calorie foods, some animals will maintain their weight by increasing the amount of food they consume, supporting a tendency to return to an established weight.

Earlier attempts to develop mathematical models of metabolic weight regulation did not specifically include the neuroendocrine signals that act on the central nervous system to control both food intake and energy expenditure. Tam's model focuses on the pathway controlled by leptin, a hormone produced by fat cells that helps to regulate energy metabolism. Although low leptin levels are a starvation signal leading to increased food consumption and reduced energy expenditure, mutations that disable the leptin pathway are extremely rare. Obese individuals usually have elevated leptin levels and show evidence of resistance to leptin's effects.