# Macrophage ERK Signaling and Its Application in Modulating Skeletal Muscle Insulin Resistance

> **NIH NIH SC2** · UNIVERSITY OF TEXAS RIO GRANDE VALLEY · 2020 · $145,300

## Abstract

PROJECT SUMMARY/ABSTRACT
 Insulin resistance precedes and contributes to the development of type 2 diabetes, and it is now believed
that chronic inflammation is the source of obesity-induced insulin resistance. Recent studies demonstrate that
mouse and human skeletal muscle have an increased macrophage population upon high fat feeding and
obesity. However, the molecular mechanisms linking macrophage accumulation in, and insulin resistance of,
the skeletal muscle are not known. One possible link is Toll-like receptor 4 (TLR4), a membrane receptor that
plays an important role in the innate immune system by activating inflammatory mediators such as extracellular
signal-regulated kinases 1 and 2 (ERK1 and ERK2). The positive regulators of TLR4 signaling after activation,
especially the endosomal transport system, remain unclear, and these may be critical in the development of
insulin resistance. The hypothesis is that ERK1 and ERK2 positively regulate TLR4-mediated inflammatory
responses and that inhibition of ERK signaling will protect against insulin resistance. In the process of pursuing
the overall project goal, the following specific aims will be addressed. Aim 1: To characterize the role of ERK1
and ERK2 in regulating TLR4 endocytosis and signaling. Using siRNA, ERK1 and ERK2 isoforms will be
knocked down in bone marrow derived macrophages to determine the molecular mechanisms regulating TLR4
endocytosis. Aim 2: To assess the contributions of inhibiting ERK signaling in macrophages to the protection
against insulin resistance, and to the regulation of skeletal muscle macrophage infiltration. Insulin clamp
studies will be performed to examine whether ERK1 and ERK2 deficiencies in macrophages result in improved
insulin sensitivity and protection against high fat diet-induced skeletal muscle inflammation and insulin
resistance in a mouse model. The proposed studies in characterizing the phenotype of macrophage ERK1 and
ERK2 will contribute to the unraveling and understanding of the specific functions of ERK1 and ERK2 isoforms.

## Key facts

- **NIH application ID:** 9888375
- **Project number:** 5SC2GM127272-03
- **Recipient organization:** UNIVERSITY OF TEXAS RIO GRANDE VALLEY
- **Principal Investigator:** SARA M REYNA
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $145,300
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888375

## Citation

> US National Institutes of Health, RePORTER application 9888375, Macrophage ERK Signaling and Its Application in Modulating Skeletal Muscle Insulin Resistance (5SC2GM127272-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9888375. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*