UW authors review three decades of weight regulation research in Science

Investigators reviewing three decades of research into body weight regulation conclude that it may not be possible to find a single effective treatment for obesity. Instead, drug therapy may have to target the multiple systems that control weight.

Drs. Stephen Woods and Randy J. Seeley, formerly of the UW and now of the University of Cincinnati Medical Center, and Drs. Daniel Porte, Jr. and Michael W. Schwartz of the UW School of Medicine review obesity research dating back to 1966 in the May 29 issue of the journal Science.

The authors focus on the molecular signals that control food intake. The research review shows that the body has numerous integrated and redundant systems for regulating weight, and that many pathways in the central nervous system participate in responding to signals informing the brain about the fat content of the body.

“While the notion of a single ‘magic bullet’ for obesity treatment is overly optimistic,” said Schwartz, “there is good news. Namely, progress into understanding of the weight control system will likely lead to drug combinations that are effective in treating obesity. We can be encouraged that treatments will improve, but we must be realistic that multiple systems must be targeted for long-term weight control to be effective. No single intervention is likely to do the trick.”

The authors cite the example of the difficulty of achieving weight loss by reducing calorie intake. When calories are cut, insulin and leptin levels decrease, and hormones secreted by the adrenal cortex (glucocoricoid or GC hormones) increase — a combination that activates nerve pathways that stimulate appetite and promote weight gain, while at the same time inhibiting pathways that have the opposite effect. These dual responses maximize the body’s tendency to find a physiological balance (homeostasis), and consequently maximize the efficiency of the body in replenishing depleted fuel stores.

“While such a robust system for defending fat stores may have conferred a survival advantage during human evolution, it now poses a formidable challenge for the treatment of obesity,” the authors state. “Individuals who suffer from a regulatory defect that results in the defense of an elevated level of body fat appear to resist changes in energy stores with the vigor characteristic of lean individuals.

“Interventions directed at multiple targets in the energy homeostasis system might be necessary to achieve and maintain weight loss.” ¶

Laurie McHale