The prevalence of obesity in most industrialized nations leads to significant health complications, such as heart disease and cancer. At the source of the problem is our inability to control food intake when presented with excess food. Animal models, including rodents, suffer from the same inability to control intake and will gain weight when exposed to rich food in excess. It is critical that we understand how reward and motivation circuits of the brain regulate food intake and the nature of the dysfunction that causes obesity. Food intake is controlled by signals that travel from the body to the brain and considerable progress has been made toward identifying molecules, such as the leptin hormone, that signal the brain to modulate food intake. Leptin is secreted from fat cells in the body and serves to communicate the state of peripheral fat stores to the brain. We are interested in trying to define the critical brain circuits that respond to leptin. While most current research has focused on leptin receptor function within the hypothalamus, we hypothesize, and present preliminary data, suggesting that leptin signals directly to dopamine neurons of the midbrain to block feeding behavior. These ventral tegmental area (VTA) neurons are known to be important modulators of motivated behavior and play a particularly important role in the development of drug addiction. We propose to characterize the nature of leptin receptor signaling in the VTA neurons and to determine how the leptin signal attenuates feeding. We will conduct molecular and electrophysiological characterization of leptin action in the VTA. In addition, animals with attenuated leptin signaling in the VTA will be analyzed for alterations in feeding behavior. These exploratory studies will establish a novel mechanism for leptin action in the brain and will contribute to our understanding of ingestive behavior. ? ? ?
| Hommel, Jonathan D; Trinko, Richard; Sears, Robert M et al. (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51:801-10 |
