Role of Central Neurotensin Signaling in the Ventral Tegmental Area for Ingestive Behavior and Body Weight

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Project Summary Overconsumption of food and reduced physical activity cause obesity, but limited understanding of the neuronal systems regulating these behaviors has hindered development of therapies to support weight loss. Intriguingly, injecting the neuropeptide neurotensin (Nts) into the ventral tegmental area (VTA) of the brain suppresses feeding and promotes physical activity, the ideal combination of behaviors for reducing weight. These effects are likely mediated via the subset of dopamine neurons within the VTA that express Neurotensin Receptor-1 (NtsR1) and indeed, activating these neurons in obese mice restrains feeding, increases physical activity, and causes weight loss. Taken together, these data suggest that augmenting Nts-NtsR1 signaling via the VTA may be useful to safely promote weight loss. Here I will test the hypothesis that endogenous or pharmacological enhancement of Nts-NtsR1 signaling will promote weight loss behaviors. In Aim 1 I will augment endogenous Nts input to the VTA. Specifically, I will combine NtsCre mice and optogenetics to activate lateral hypothalamic area neurotensin (LHANts) neurons projecting to the VTA, which have been implicated in promoting weight loss. However, activating all LHANts neurons simultaneously invokes voracious drinking (putatively via projections elsewhere) that mitigates weight loss. My work will reveal if isolating the endogenous LHANts VTA NtsR1 circuit can optimally promote weight loss, without invoking undesirable effects. In Aim 2 I will determine if pharmacological NtsR1 agonists promote weight loss behaviors. NtsR1 is a G-Protein Coupled Receptor that, upon ligand binding to the receptor, can transduce intracellular signaling via Gq-coupled and/or a ß-arrestin pathways, but it remains unclear if one or both of these pathways potentiate weight loss effects. To assess which NtsR1 receptor signaling pathway invokes weight loss, I will administer a general NtsR1 agonist that promotes both Gq-coupled and ß-arrestin signaling or a compound that exclusively activates the ß-arrestin pathway. Agonists will be delivered intra-VTA or systemically to elucidate the brain site and intracellular pathways by which NtsR1 agonism mediates weight loss. Taken together, these data will reveal endogenous and pharmacological mechanisms by which Nts-NtsR1 modulates body weight and may be useful to guide future development of strategies to treat obesity.