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

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2021 · $306,206

## Abstract

Project Summary
 Aging is associated with increased adiposity, that induces low grade chronic inflammation in many
tissues, termed “inflamm-aging”. This metabolically-triggered inflammation, aka "meta-inflammation", underlies
pathological processes of many age-associated diseases and is a hallmark of aging. Macrophages are a major
immune-mediator of meta-inflammation. Macrophages consist of pro-inflammatory M1 and anti-inflammatory M2
cells, which undergo dynamically polarization to either M1 and M2 state in response to environmental cues.
Macrophage polarization is impaired in aging, which contributes to inflamm-aging. Macrophage anti-
inflammatory reprogramming has potential to prevent/reverse meta-inflammation in aging. However, the
regulatory mechanisms of macrophage polarization are not well understood. Growth hormone secretagogue
receptor (GHS-R), is a known receptor for nutrient-sensing gut hormone ghrelin. We have found that global GHS-
R ablation protects against obesity, insulin resistance, adipose tissue inflammation and nonalcoholic
steatohepatitis (NASH) in aging. GHS-R is highly expressed in macrophages and its expression increases in
aging. In contrast, GHS-R expression is undetectable in hepatocytes and very low in adipocytes. Our gene
knockdown study indicates that GHS-R has cell-autonomous effects in macrophages. Our preliminary data have
suggested that GHS-R deletion down-regulates key insulin signaling mediators insulin receptor substrate-2
(IRS2) and protein kinase Akt in macrophages. Hence, we hypothesize that GHS-R is a key regulator of
macrophage polarization in aging. Specifically, GHS-R activates the IRS2-Akt pathway to metabolically
reprogram macrophages to promote pro-inflammatory polarization during aging, leading to meta-
inflammation in adipose tissues and liver. To unravel the roles and pertinent mechanisms of GHS-R in
macrophage reprogramming and meta-inflammation, we have generated myeloid-specific GHS-R knockout and
re-expressing mice. The following comprehensive and complementary Specific Aims will be tested: 1. Determine
the role of GHS-R in macrophage polarization, and its effect on adipose and hepatic meta-inflammation during
aging (in vivo studies); 2. Interrogate the cellular mechanisms by assessing cell-autonomous effect of GHS-R in
macrophages, and paracrine effect of GHS-R deficient/re-expressing macrophages on adipocytes and
hepatocytes (ex vivo studies); 3. Delineate molecular mechanisms by which GHS-R regulates macrophage
polarization. We anticipate that during aging, GHS-R activates insulin signaling pathway to upregulate anabolic
glycolysis and down-regulate fatty acid oxidation pathways, thus promoting pro-inflammatory polarization. This
proposal will shed light on a new paradigm for metabolic reprogramming of macrophages during aging, and will
likely uncover a novel regulatory mechanism linking nutrient sensing signaling and metabolic regulatory
pathways in macrophages. This proposal will also pr...

## Key facts

- **NIH application ID:** 10168431
- **Project number:** 5R01AG064869-03
- **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:** $306,206
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168431

## Citation

> US National Institutes of Health, RePORTER application 10168431, Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging (5R01AG064869-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168431. Licensed CC0.

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