Increased energy consumption is a major contributing factor to the current obesity epidemic. Therefore, regulating food intake is a primary target for therapeutic approaches to prevent or treat obesity and its co-morbidities. Despite considerable research into the area of food intake regulation, the mechanisms underlying hypothalamic nutrient sensing remain largely unknown. Specific neurons in the hypothalamus sense both glucose and fatty acids, as recently shown, to regulate food intake. However, it is unknown if glucose or fatty acids regulate food intake through the same mechanism or if their effects are interdependent.
We hypothesize that the composition and metabolism of a specific class of metabolites, acyl-CoAs, common to both glucose and lipid metabolic pathways is the key signaling molecule responsible for mediating glucose- or fatty acid-induced changes in food intake. To test our working hypothesis, we propose research that relies on the distinct expertise of two laboratories and employs multifaceted approaches that combine the fortes of each laboratory. We expect these studies to significantly advance our understanding into the basic mechanisms governing nutrient sensing and food intake regulation and to provide a solid foundation from which to base further grant solicitation.
Hypothesis and Specific Aims:
We hypothesize that the source, composition and content of acyl-CoAs in the hypothalamus are key mediators in neural energy metabolism and signaling, and food intake regulation. To test our hypothesis, we will:
determine how the source (de novo vs. exogenous) and composition of acyl-CoAs affect intracellular metabolism and control of food intake and
test the effects of overexpressing mitochondria) glycerol-3-phosphate acyltransferase (mtGPAT), the first enzyme in glycerolipid synthesis, in the hypothalamus on altering fatty acid (FA) and acyl-CoA metabolism and, subsequently, neural signaling and food intake.
ZEB1 and the Development of Obesity
Oxyntomodulin and the Regulation of Non-Exercise Activity Thermogenesis
Hypothalamic Acyl-CoA Metabolism and Food Intake Regulation
Parents as the Agent of Change for Childhood Obesity
Identifying Novel Roles of Lipocalin 2 in Insulin Action and Glucose Metabolism
GIRK$: A New Obesity Gene?
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