# Glucose inhibited neurons in the control of brown and white adipose tissue

> **NIH NIH F31** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $40,243

## Abstract

Project Summary
Over the past several decades a role for adaptive thermogenesis in brown adipose tissue (BAT) and beiging of
white adipose tissue (WAT) has emerged as a potential therapeutic avenue to combat human obesity.
However, the brain circuitry that controls BAT and WAT has not been fully mapped. Determining the neural
pathway that controls both BAT and WAT beiging is the first step toward safely manipulating these tissues to
combat obesity. As obesity has a higher prevalence in females, it is one goal of this study to examine the
neural mechanism underlying BAT thermogenesis and WAT beiging in females. In females only, bone
morphogenic protein 8B (BMP8B) injection in the ventromedial hypothalamus (VMH) increased orexin (OX)
expression in downstream lateral hypothalamic (LH) neurons, BAT thermogenesis and WAT beiging. This
effect of BMP8B was blocked by LH OX receptor antagonists, was dependent on circulating ovarian estrogens
and required inhibition of the cellular fuel sensor AMP-activated protein kinase (AMPK) in the VMH. We have
already shown that estrogen blunts activation of the ventrolateral VMH (vlVMH) glucose inhibited (GI) neurons
in low glucose by inhibiting AMPK. Interestingly, estrogen receptors are densely clustered in the vlVMH.
Further, GI neurons make up ~60% of the neurons in the vlVMH. There is a high correlation between VMH
neurons that produce nitric oxide (NO) in response to low glucose and GI neurons. Moreover, VMH GI neurons
require neuronal nitric oxide synthase (nNOS) to sense glucose. These data lead us to hypothesize that vlVMH
nNOS-GI neurons exert a tonic inhibition of the downstream LH OX neurons which activate BAT
thermogenesis and WAT beiging. Further, that BMP8B, like estrogen, increases the inhibitory effect of glucose
on vlVMH GI neurons allowing BAT thermogenesis and WAT beiging to increase. To test this hypothesis, the
applicant will first use a combination of electrophysiological recordings, optogenetics and virally assisted circuit
mapping in mice expressing cre-recombinase in nNOS neurons to examine the neural connection between the
vlVMH nNOS-GI and LH OX neurons in vitro. Based on the literature she will determine whether inhibitors of
group III metabotropic glutamate receptors (mGluR) and/or GABA receptors mediate the inhibitory effect of
vlVMH nNOS-GI neurons on LH OX neurons. She will then use chemogenetics in nNOS cre mice to determine
how VMH nNOS neurons regulate BAT thermogenesis and WAT beiging in vivo. Finally, she will determine
whether BMP8B directly regulates vlVMH nNOS-GI neurons which project to the LH. This project will uncover
the neural mechanisms by which estrogen and BMP8B increase BAT thermogenesis and WAT beiging in
females. These data are important for developing therapies to counter the increased incidence of obesity and
metabolic disorders in post-menopausal women.

## Key facts

- **NIH application ID:** 10207513
- **Project number:** 5F31DK126433-02
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Pamela Renee Hirschberg
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,243
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207513

## Citation

> US National Institutes of Health, RePORTER application 10207513, Glucose inhibited neurons in the control of brown and white adipose tissue (5F31DK126433-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10207513. Licensed CC0.

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