Leptin was identified as a potential feedback signal in the regulation of energy balance in 1994, but little progress has been made in using leptin to prevent or reverse human obesity. This may be due to a failure to fully understand the central mechanisms by which leptin can control food intake which can only be evaluated when they are functioning normally. Control of energy balance is often investigated in models in which components of the system have been genetically modified, the animal has been fed an obesogenic diet or pharmacologic doses of leptin are used to investigate an endogenous physiologic system. Preliminary data using threshold doses of leptin in normal weight animals demonstrate the presence of a leptin sensitive pathway that inhibits food intake when circulating leptin concentrations rise above basal levels as a signal of positive energy balance. We have demonstrated that activation of leptin receptors in the hindbrain nucleus of the solitary tract (NTS) lowers the threshold for activation of hypothalamic leptin receptors through a neural network. This effect is most dramatic in the dorsomedial ventromedial nucleus of the hypothalamus (VMHdm), where there is a 3-fold increase in leptin receptor activation. Additional experiments demonstrated that loss of NTS leptin-receptor expressing cells raised the threshold for a hypothalamic response to leptin and that loss of leptin receptor expressing cells in the VMHdm abolished weight loss caused by hindbrain infusions of leptin. Based on these data and evidence that hypothalamic leptin suppresses food intake by amplifying the response to peripheral satiety signals, we hypothesize that small increases in circulating leptin amplify the response to peripheral satiety signals through a circuit in which NTS leptin enhances VMHdm leptin sensitivity. This application will establish the function and anatomy of the hypothesized network. The first Aim will test whether activation of VMHdm leptin receptors amplifies the response to peripheral satiety signals. The second Aim will test whether these receptors protect against diet-induced obesity. The third Aim will use tract tracing to identify the organization of the proposed neural network and in situ hybridization to identify the neurochemical phenotype of leptin receptor-expressing neurons in the NTS and VMHdm. Successful completion of these Aims will provide new information on the synergy between long-term signals of energy balance and peripheral short-term satiety signals as an integral component of a network that facilitates precise control of energy balance.