Mechanisms of action for dorsomedial hypothalamic Lepr-Glp1r neurons that control feeding and energy balance

NIH RePORTER · NIH · F31 · $48,644 · view on reporter.nih.gov ↗

Abstract

ABSTRACT Obesity promotes type 2 diabetes and other adverse health outcomes, placing a significant burden on our healthcare institutions- as well as patients with obesity. The brain contains systems that modulate feeding and body weight over the long term. Many of these systems reside in the hypothalamus, which controls food intake and energy homeostasis in response to a host of signals, including leptin (a hormonal signal of body energy stores) and feeding-activated neurons in the brainstem nucleus tractus solitarius (NTS). To design new therapies to combat obesity we must understand the brain systems that control feeding and body weight, including the hypothalamic circuits that integrate input from leptin and the hindbrain. Prior work demonstrated that GABAergic Lepr neurons that reside in the dorsomedial hypothalamus (DMH) make important contributions to the control of feeding behavior, including in the suppression of orexigenic arcuate nucleus (ARC) AgRP neurons by leptin and feeding. Additionally, our recent results showed that several populations of food intake-suppressing glutamatergic NTS neurons project to the DMH and inhibit AgRP neurons. While these finding suggest that a population of GABAergic DMH LepRb neurons integrates signals from leptin and the NTS to suppress food intake by inhibiting AgRP neurons, the DMH contains many populations of neurons with different functions, including multiple groups of GABAergic LepRb neurons. Our laboratory used single nucleus RNA sequencing to identify known and novel populations of LepRb neurons, including a novel population of GABAergic DMH LepRb neurons marked by glucagon-like peptide 1 (GLP-1) receptor (Glp1r) expression (LepRbGlp1r neurons). We found that LepRbGlp1r neurons play essential roles in the control of food intake by leptin. We hypothesize that these LepRbGlp1r neurons represent the crucial population of GABAergic DMH LepRb neurons that integrate signals from leptin and the NTS to suppress food intake by inhibiting AGRP neurons. To test this overall hypothesis, we will test the notions that: (1) DMH LepRbGlp1r neurons receive direct excitatory input from glutamatergic NTS neurons; (2) LepRbGlp1r neurons inhibit AgRP neurons and suppress food intake; and (3) silencing LepRbGlp1r neurons will increase the activity of AgRP neurons and promote feeding and weight gain.

Key facts

NIH application ID
10909055
Project number
5F31DK137390-02
Recipient
UNIVERSITY OF MICHIGAN AT ANN ARBOR
Principal Investigator
Allison Duensing
Activity code
F31
Funding institute
NIH
Fiscal year
2024
Award amount
$48,644
Award type
5
Project period
2023-07-01 → 2026-06-30