The increasing incidence of obesity is a major health issue facing the USA. Fortunately, in the pastdecade several key hormones and CMS pathways controlling body weight and glucose homeostasis havebeen identified. Indeed, we now have a rough CMS roadmap through which key metabolic signals suchas leptin exert its effects. If effective strategies to combat the incidence of obesity and eating disordersare to be developed, an increased understanding of the molecular mechanisms underlying coordinateenergy homeostasis is required. Recently, we have assembled a team of investigators whose goal is todelineate the neural substrates underlying coordinated control of food intake, body weight and glucosehomeostasis. In the current application, we provide a series of studies designed to increase ourunderstanding of the hypothalamic control of liver metabolism. We will also investigate mechanisms bywhich the hypothalamus regulates complex feeding behavior, especially the rewarding nature of high fatdiets. First, we will investigate mechanisms by which leptin and serotonin acting on hypothalamic POMCneurons regulate hepatic glucose and lipid metabolism. Second, we will investigate the interaction ofhypothalamic pathways controlling body weight with the brain pathways regulating complex appetitivebehavior and reward. We hypothesize that these reciprocal connections are crucial for regulatingresponses to natural rewards including high fat diet. Finally, in parallel to our mouse studies in Aims 1-2,we will, in postmortem human brain tissue, quantitatively assess alterations in genes whose expressionwe hypothesize is altered in obese humans and those with drug-induced metabolic syndrome. The timelytranslation of hypotheses based on animal models to the human is one of the primary goals of theTaskforce on Obesity at UT Southwestern Medical Center at Dallas, and we are uniquely poised to makemajor strides in translational research of obesity.
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