# Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2021 · $53,025

## Abstract

Project Summary
 Chronic over-nutrition and obesity induce low-grade inflammation in tissues such as adipose tissue and
liver, the inflammation leads to further metabolic dysfunctions in these tissues. This metabolically-triggered
inflammation is termed "meta-inflammation", which underlies pathological processes of many chronic diseases
such obesity, insulin resistance, and diabetes. Macrophages are key immune-modulators of meta-inflammation,
comprised of two main subtypes: pro-inflammatory M1 and anti-inflammatory M2. Emerging evidences suggest
that promoting macrophage anti-inflammatory polarization has exciting potential for reversing the pathology of
meta-inflammation. However, the regulatory mechanisms of macrophage polarization are not well understood.
G-protein-coupled receptor, growth hormone secretagogue receptor (GHS-R), is a known receptor for nutrient-
sensing gut hormone ghrelin. Ghrelin promotes obesity and insulin resistance. Global GHS-R ablation protects
against diet-induced obesity and insulin resistance in aging, showing reduced inflammation in adipose tissue
and liver. Cell-based studies further suggest that GHS-R has cell-autonomous effects in macrophages, and
GHS-R knockdown decreases endotoxin-induced macrophage pro-inflammatory shift. The hypothesize of this
proposal is that GHS-R is a key regulator of meta-inflammation, contributing to the pathogenesis of
obesity and nonalcoholic steatohepatitis (NASH); GHS-R reprograms macrophage polarization toward a
pro-inflammatory state, leading to inflammation and metabolic dysfunctions in adipose tissue and liver.
To unravel the roles and pertinent mechanisms of GHS-R in macrophage polarization, newly-generated myeloid-
specific GHS-R knockout mice will be used. The following comprehensive and complementary Specific Aims will
be conducted: 1. Determine whether GHS-R promotes pro-inflammatory polarization of macrophages, and
increases inflammation and lipid deposition in adipose tissue and liver (in vivo studies). 2. Examine whether
GHS-R cell-autonomously regulates macrophage polarization, and GHS-R activation in macrophages promotes
inflammation and enhances lipotoxicity in adipocytes and hepatocytes via endocrine and/or paracrine actions
(ex vivo studies). 3. Investigate molecular mechanisms involved in GHS-R mediated macrophage polarization.
We postulate that GHS-R metabolically reprograms macrophages; GHS-R, via insulin signaling, modulates
signaling pathways to govern fatty acid oxidation, glucose metabolism, and mitochondrial function of
macrophages. This proposal will shed light on a new paradigm for regulating macrophage polarization, and will
likely uncover a novel regulatory mechanism linking nutrient sensing, inflammation and metabolism. This
proposal will also provide “proof-of-concept” evidence for whether targeting GHS-R in macrophages would be a
unique and powerful strategy for combating obesity and inflammation.

## Key facts

- **NIH application ID:** 10436515
- **Project number:** 3R01AG064869-03S2
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** YUXIANG SUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $53,025
- **Award type:** 3
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436515

## Citation

> US National Institutes of Health, RePORTER application 10436515, Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging (3R01AG064869-03S2). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10436515. Licensed CC0.

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