Coordination of food intake and utilization of nutrient stores is referred to as """"""""energy homeostasis"""""""". When this fundamental process is disrupted, it can lead to a number of disorders, in particular, obesity, anorexia and diabetes. I found that a ligand of the JAK/STAT pathway in flies, called Unpaired2 (Upd2), functions like Leptin in fruit flies. It signals the organism's fat status to GABAergic neurons in the brain. Current working model suggests that JAK/STAT signaling promotes insulin secretion by relieving the inhibitory tone of GABA neurons on insulin producing cells (IPCs). This circuit module is strikingly reminiscent to that used by Leptin to control energy balance in the mammalian system. In this proposal, using the Drosophila system Leptin model, I propose to investigate the following: i) how fat levels regulate Upd2 at the level of secretion;ii) identify mechanism(s) by which Leptin and Upd2 signaling affects GABAergic neuronal firing are unknown. I will test whether the role for STAT in GABAergic neurons is transcriptional or post- transcriptional. Then, I will identify STAT's targets and/or its protein interactors which are involved in Upd2- mediated regulation of GABA neurons;iii) finally, using an innovative technique, I plan to identify neurons which respond to particular sorts of diets and determine the molecular profile of such neuronal groups. This is expected to provide information about the cellular identify of the neuronal group which responds to dietary changes. This will guide subsequent studies of how a particular set of neurons influence systemic energy metabolism in response to specific diets. Overall, the proposed aims will address two key issues in Leptin Biology: i) how adipostatic molecules are regulated at the level of translation and secretion in response to changes in nutrient stores;ii) what molecular mechanisms are deployed by these molecules to alter neuronal physiology in response to dietary changes. The 2010 policy document-Dietary guidelines for Americans- issued by the USDA finds that, an increased intake of fats, sugars and refined grains in lieu of protein-rich food, is a primary cause of chronic diseases such as cardiovascular disorders, diabetes and some forms cancer. In order to negate the effects of high fat and sugar diets, elucidating the molecular basis of systemic fat metabolism is crucial. The studies I propose here have the potential to illuminate why we prefer fat-rich foods to a protein-rich diet and importantl will provide relevant insights for the treatment of complex metabolic disorders.

Public Health Relevance

Humans with loss of Leptin function are clinically obese and suffer from complex metabolic disorders, because of their inability to regulate appetite, energy expenditure and burn the excess fat stores. My studies find that a molecule called Unpaired 2 (Upd2) in flies, which is structurally similar to Leptin, is involved in maintaining energy homeostasis. Human Leptin can substitute for an Upd2 deficit in fruit flies, because it uses the same set of molecules and neural circuits;hence, further studies using flies can illuminate how fats are sensed and has significant implications for the treatment of human metabolic disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Career Transition Award (K99)
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Digestive Diseases and Nutrition C Subcommittee (DDK)
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Hyde, James F
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Harvard Medical School
Schools of Medicine
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Rajan, Akhila; Housden, Benjamin E; Wirtz-Peitz, Frederik et al. (2017) A Mechanism Coupling Systemic Energy Sensing to Adipokine Secretion. Dev Cell 43:83-98.e6