Much as the stomach rumbles, it's really the brain that tells us how much to eat. The brain takes its cue partly from a hormone released by fat cells, called leptin, that has inspired serious awe among obesity researchers. Their respect for leptin should become even deeper: Two studies in today's issue of Science show that the hormone can rewire part of the brain that regulates appetite. The results shed new light on how metabolism goes awry in obesity.
Obesity now kills some 400,000 Americans a year--more than everything else but tobacco. To help prevent and treat it, researchers want to grasp exactly how the body regulates its weight. Obesity researchers knew that fat cells released the hormone leptin into the blood, and that it traveled to the hypothalamus, a structure in the base of the brain that regulates feeding and other basic functions. There, leptin alters the moment-to-moment activity of neurons to reduce appetite. But neuroendocrinologists Tamas Horvath of Yale University, Jeffrey Friedman of Rockefeller University, and their colleagues suspected that leptin could have a more lasting effect on the neurons.
To investigate, they took leptin-deficient mutant mice that grow five times as fat as normal mice do, then injected them with leptin. Two days later, they examined appetite-stimulating and appetite-suppressing neurons from the arcuate nucleus, a region of the hypothalamus that helps regulate body weight. In the obese mutants, a single dose of leptin reduced by 85% the synapses that normally boost appetite-stimulating neurons and doubled the synapses that block them. On balance, leptin had rewired the neurons to reduce appetite. It also rewired appetite-suppressing neurons to increase their activity.
The second study finds an even more fundamental role for leptin. Neurobiologist Richard Simerly of the Oregon Health and Science University in Beaverton and colleagues report that leptin has a hand in wiring the hypothalamus during development. The team counted dye-labeled axons--the extensions neurons use for communication--in the arcuate nucleus of normal and mutant mice. The arcuate nucleus of normal baby mice had 10 times as many axons as did mutant mice lacking leptin, but injecting the leptin-deficient mutants with leptin restored normal brain development. The results suggest that in baby mice, leptin spurs neurons to send out feelers and form contacts, hard-wiring connections that will later regulate food intake.
The research is "excellent work" demonstrating that leptin can alter the brain's wiring diagram, says endocrinologist Jeffrey Flier of Harvard Medical School. Moreover, he says, leptin's role in brain development suggests that the hormone may play a role in establishing an individual's set point--the particular weight he or she tends to maintain.