# Hypothalamic Grb10 and body weight

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $492,297

## Abstract

Obesity is a major risk factor for type II diabetes and metabolic syndromes. Increased understanding of
body weight regulation may lead to effective strategies to combat obesity and diabetes. Hypothalamic
neurons, including anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic Agouti-related
peptide (AgRP) neurons, integrate multiple metabolic cues (e.g. leptin and insulin) to provide a coordinated
control of energy and glucose homeostasis. We found that an adaptor protein, growth factor receptor-bound
protein 10 (Grb10), is abundantly expressed in the hypothalamus, and its expression is elevated by HFD
feeding. Further, Grb10 inhibits both leptin and insulin actions in neurons. Importantly, deletion of Grb10 in
hypothalamic neurons leads to profound lean phenotypes in mice. Based on these, we hypothesized that
Grb10 promotes body weight gain by negative regulation of leptin and insulin signaling in
hypothalamic neurons. The first objective will focus on anorexigenic POMC neurons. We will generate two
opposite genetic mouse models: one with Grb10 deleted in mature POMC neurons and the other with Grb10
overexpressed in mature POMC neurons. We will use these loss- and gain-of-function models to determine
how Grb10 in POMC neurons regulates energy and glucose balance, modulates leptin and/or insulin
signaling pathways, and controls firing activities and gene expression. The second objective will focus on
orexigenic AgRP neurons. We will use the similar approaches to delete or overexpress Grb10 in mature
AgRP neurons. We will use these loss- and gain-of-function models to determine the physiological role of
Grb10 in AgRP neurons in the regulation of energy/glucose balance. Further, we will explore the cellular and
molecular mechanisms by which Grb10 modulates leptin/insulin-induced signaling pathways and regulates
firing activity and gene transcription of AgRP neurons. The third objective is to use in vitro approaches to
determine the molecular mechanisms for Grb10 to inhibit leptin signaling. To this end, we will first map the
interacting regions between Grb10 and the leptin receptor molecules, and then determine if such interaction
provides a mechanism for Grb10 to inhibit leptin signaling. These studies could lead to important advances
in our understandings regarding the central regulation of energy/glucose homeostasis. We may also provide
mechanistic insights on the fundamental biology for leptin/insulin signaling in the brain. Finally, the proposed
studies may carry translational impact on human health, as we may identify brain Grb10 as a rational target
for potential anti-obesity therapy.

## Key facts

- **NIH application ID:** 9935056
- **Project number:** 5R01DK115761-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** ALAN FRAZER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $492,297
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935056

## Citation

> US National Institutes of Health, RePORTER application 9935056, Hypothalamic Grb10 and body weight (5R01DK115761-03). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9935056. Licensed CC0.

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