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.
