Project Details
Description
Project Summary/Abstract
Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy homeostasis.
Glucagon-like peptide 1 (GLP-1, encoded by Gcg), secreted by a distinct population of neurons located within
the
Nucleus Tractus Solitarius, suppresses feeding. Central and peripheral GLP-1 work independently to
suppress feeding
. However, the cellular and circuit mechanisms mediating endogenous GLP-1 action in the CNS
are still poorly understood. This is mainly due to the presence of diverse neuronal subtypes, complex central
neuronal connectivity, and the lack of molecular tools that can directly detect GLP-1 release in the brain.
Addressing the CNS mechanism of GLP-1 will help develop more tailored treatment for intervention of obesity.
Our overarching goal is to gain a mechanistic understanding of endogenous GLP-1 release and its functions in
the CNS in a cell type- and circuit-defined manner. In a previous study,
we found that NTS GLP-1 projection to
the paraventricular hypothalamic nucleus (PVN) enhances glutamatergic synaptic transmission, which is
sufficient to suppress food intake, and ablation of PVN GLP-1R causes overeating and obesity. These results
highlight the potential role of central GLP-1 in regulating energy homeostasis. However, GLP-1 signaling is
complex due to the heterogeneity of PVN region GLP-1R neurons which form synapses with the dorsal motor
nucleus of the vagus nerve (DMV) neurons and release glutamate, while also releasing g-aminobutyric-acid in
the bed nucleus of stria terminalis (BNST). DMV and BNST may mediate food intake behavior differentially, i.e.
homeostatic vs. hedonic feedings, but the roles that the PVN GLP-1R neurons-to-DMV and BNST projections
play remains unexplored. Moreover, using our recently developed optical sensors for GLP-1, termed Reporter
for Transmission mediated by G protein-coupled Receptor, we found the timing of GLP-1 release into the PVN
is inversely related to eating bouts. We thus hypothesize that circuit and neuronal subtype-dependent
endogenous GLP-1 signaling in the PVN regulates eating patterns (e.g. meal timing and sizes), energy
expenditure, and food rewards. To test this hypothesis, we will determine the temporal dynamics of GLP-1
release and neuronal activity in the PVN during feeding episodes; and we will test the hypothesis that GLP-1
signaling regulates homeostatic and motivational feeding via different neuronal pathways. The results of this
study will advance our conceptual understanding of the regulatory effects of endogenous GLP-1, facilitating the
development of neuropeptide-targeting clinical interventions for eating disorders and obesity.
Status | Active |
---|---|
Effective start/end date | 7/5/22 → 4/30/25 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $484,389.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $472,379.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $466,296.00
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