The Role of the Hindbrain in Leptin Action

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DESCRIPTION (provided by applicant): Leptin is an adipocyte hormone that signals the brain about peripheral energy stores. Animals and humans that lack leptin are hyperphagic and morbidly obese. Both intravenous and intracerebroventricular (lateral and third ventricle) leptin administration reduce food intake and body weight demonstrating that leptin passes across the blood-brain barrier to act at its receptors in the CNS to exert these effects. While most attention has been paid to leptin receptors in the hypothalamus, the potential role of leptin action in the hindbrain has received little investigation. In order to determine the contribution of the hindbrain in mediating the effects of leptin, it is important to determine if leptin action in the brainstem is direct or indirect. While demonstration of the specific expression of the long-form leptin receptor in the hind brain has proven technically challenging, activation of suppressor of cytokine signaling-3 (SOCS-3) can be used to determine hindbrain neurons that are directly activated by leptin. To determine whether leptin acts directly in the brainstem, we will assess SOCS-3 expression in the brainstem following both peripheral and central leptin administration. Next, the connectivity of the hindbrain leptin-responsive neurons to the feeding centers of the forebrain will be established using tract tracing methods in combination with assessments of leptin-induced gene expression. We will also characterize the neurochemical phenotype and the central projections of these leptin responsive brainstem neurons. When these neuroanatomical data are combined with functional data on 4th ventricle leptin administration, critical information about how extrahypothalamic sites contribute to the important actions of leptin to regulate energy balance will be uncovered.