HYPOTHALAMIC GRB 10 AND BODY WEIGHT

Obesity is a major risk factor for type II diabetes and metabolic syndromes. Increased understanding ofbody weight regulation may lead to effective strategies to combat obesity and diabetes. Hypothalamicneurons, including anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic Agouti-relatedpeptide (AgRP) neurons, integrate multiple metabolic cues (e.g. leptin and insulin) to provide a coordinatedcontrol of energy and glucose homeostasis. We found that an adaptor protein, growth factor receptor-boundprotein 10 (Grb10), is abundantly expressed in the hypothalamus, and its expression is elevated by HFDfeeding. Further, Grb10 inhibits both leptin and insulin actions in neurons. Importantly, deletion of Grb10 inhypothalamic neurons leads to profound lean phenotypes in mice. Based on these, we hypothesized thatGrb10 promotes body weight gain by negative regulation of leptin and insulin signaling inhypothalamic neurons. The first objective will focus on anorexigenic POMC neurons. We will generate twoopposite genetic mouse models: one with Grb10 deleted in mature POMC neurons and the other with Grb10overexpressed in mature POMC neurons. We will use these loss- and gain-of-function models to determinehow Grb10 in POMC neurons regulates energy and glucose balance, modulates leptin and/or insulinsignaling pathways, and controls firing activities and gene expression. The second objective will focus onorexigenic AgRP neurons. We will use the similar approaches to delete or overexpress Grb10 in matureAgRP neurons. We will use these loss- and gain-of-function models to determine the physiological role ofGrb10 in AgRP neurons in the regulation of energy/glucose balance. Further, we will explore the cellular andmolecular mechanisms by which Grb10 modulates leptin/insulin-induced signaling pathways and regulatesfiring activity and gene transcription of AgRP neurons. The third objective is to use in vitro approaches todetermine the molecular mechanisms for Grb10 to inhibit leptin signaling. To this end, we will first map theinteracting regions between Grb10 and the leptin receptor molecules, and then determine if such interactionprovides a mechanism for Grb10 to inhibit leptin signaling. These studies could lead to important advancesin our understandings regarding the central regulation of energy/glucose homeostasis. We may also providemechanistic insights on the fundamental biology for leptin/insulin signaling in the brain. Finally, the proposedstudies may carry translational impact on human health, as we may identify brain Grb10 as a rational targetfor potential anti-obesity therapy.