# The role of regulator of G protein signaling Gbeta5-R7 in neuronal control of body weight

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $492,777

## Abstract

Obesity is a major co-morbidity factor in diabetes, cancer, cardiovascular, neurological and other
diseases. Recently, a new group of human genes was linked to obesity, the genes encoding the R7 family
of regulator of G protein signaling proteins (RGS6, 7, 9 and 11) and Gnb5, which encodes the atypical G
protein beta subunit Gb5. This proposal studies how a deficiency in the Gnb5 and R7 genes can lead to
obesity and other abnormalities in control of body weight. The ultimate goal is to discover effective
treatments of disorders associated with neuroendocrine pathways regulated by these genes.
 The proposed research plan builds upon earlier discoveries that together constitute a strong
premise for this study. Gb5 and R7 proteins form obligatory dimers, so that the Gnb5 knockout causes
complete degradation of the entire Gb5-R7 complex. Ablation of one Gnb5 allele leads to obesity and
metabolic syndrome in mice; this finding was later confirmed by human genetics. Subsequent mechanistic
investigations in this lab identified a novel role for the Gb5-R7 complex in pancreatic beta cells where Gb5-
R7 strongly promoted secretion of insulin. Brain is the main organ regulating body weight, and the
expression level of Gb5-R7 is much higher in the CNS than in the pancreas or any other peripheral tissues.
These considerations lead us to the hypothesis that Gb5-RGS7 regulates body weight via its function in
the neurons, where, similarly to the insulin-secreting beta cells, it controls secretion of neurotransmitters
and hormones. In support of this hypothesis, recent studies in the lab demonstrated that local knockout of
Gnb5 in the adult mouse hypothalamus dramatically increased body and adiposity. The proposed
experiments will develop this discovery through a series of experiments performed at the organismal,
tissue and cellular levels. Specific Aim 1 will use the Cre-loxP approach to inactivate Gnb5 in specific
hypothalamic nuclei and types of neurons and examine the effect of the knockout on body weight and
metabolism. Overexpression of Gnb5 using viral gene transfer will be performed to rescue the changes
caused by the knockout. Aim 2 will study co-expression of Gnb5 with GPCRs and gene encoding
hypothalamic hormones and tissue slices will be examined ex vivo for signal-stimulated secretion of
specific hormones. Specific Aim 3 will study Gb5-R7 its knockout (CRISPR/Cas9), knockdown and
overexpression in cell lines that endogenously express Gb5-R7. Experiments will utilize pharmacological
agents and structure-function analysis to interrogate molecular events in signaling and secretory pathways.
The proposed investigation of the Gb5-R7 complex will elucidate the novel mechanism regulating secretion
of hypothalamic hormones and significantly advance our understanding of G protein signaling, etiology of
obesity and other metabolic and neuroendocrine disorders.

## Key facts

- **NIH application ID:** 10539336
- **Project number:** 5R01DK126735-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Vladlen Z Slepak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $492,777
- **Award type:** 5
- **Project period:** 2021-01-28 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539336

## Citation

> US National Institutes of Health, RePORTER application 10539336, The role of regulator of G protein signaling Gbeta5-R7 in neuronal control of body weight (5R01DK126735-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10539336. Licensed CC0.

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