Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance

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DESCRIPTION (provided by applicant): Neurons in the lateral hypothalamic area (LHA) exert opposing control of feeding and energy balance via incompletely understood neuronal circuits. Many LHA neurons express orexigenic neuropeptides and regulate limbic brain regions, including midbrain dopamine (DA) neurons, to induce hedonic feeding and promote weight gain. A separate population of LHA neurons expresses the anorectic neuropeptide neurotensin (Nts) and these LHA Nts neurons are selectively activated by stimuli that suppress feeding. Loss of action via LHA Nts neurons promotes overeating and blunts energy expenditure and DA signaling that leads to obesity, suggesting that LHA Nts neurons interface with DA circuits to regulate energy balance. Indeed, LHA Nts neurons synaptically regulate the midbrain, where many DA neurons express the receptors for neurotensin, neurotensin receptor-1 (NtsR1) and neurotensin receptor-2 (NtsR2). Nts acts via these receptors to activate DA neurons and suppress feeding, but loss of Nts action via NtsR1 promotes hedonic feeding and obesity. Collectively, these data implicate a novel LHA Nts neuronal circuit that synergizes anorectic cues and DA signaling to promote weight loss. To determine the mechanism(s) by which LHA Nts neurons regulate energy balance this proposal combines the use of novel genetic reagents and state of the art molecular tools to interrogate the constituent neurons within the LHA Nts neuronal circuit. Aim 1 will establish the LHA Nts neuronal mechanisms that coordinate physiologic cues and behavior to adaptively regulate energy balance. Aim 2 will determine how LHA Nts neurons interface with DA circuits, testing the hypothesis that Nts action via midbrain NtsR1 and/or NtsR2 neurons modulates DA signaling to regulate energy balance. Aim 3 will selectively activate LHA Nts neurons to test the hypothesis that action via the LHA Nts neuronal circuit suppresses hedonic intake and promotes locomotor activity to induce weight loss. Collectively, these studies will determine the precise mechanisms by which LHA Nts neurons regulate DA- mediated feeding and energy expenditure, and the potential for modulation of this circuit in treating obesity.