# GLP-1 Therapy:  The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $194,792

## Abstract

PROJECT SUMMARY/ABSTRACT
Incretins, the analogs of glucagon-like peptide-1 (GLP-1), improve glucose control in type 2 diabetes mellitus
and counteract obesity through mechanisms that are not completely understood. Our preliminary data show that,
in prediabetic patients and mice, GLP-1 analog therapy induces an increase in plasma IL-6, a cytokine activating
STAT3 signaling, which induces brown (beige) adipocyte differentiation in adipose tissue (AT). We discovered
that plasma IL-6 induction occurs through GLP-1 receptor (GLP-1R) stimulation in leukocytes. Interestingly,
studies in rodents indicate that GLP-1 / GLP-1R signaling also induces AT beiging. Based on these observations,
we hypothesize that incretins induce AT browning in part via transient IL-6 / IL-6R / STAT3 signaling. Our primary
objective is to further elucidate the role of IL-6 and GLP-1 signaling in mediating beneficial metabolic effects of
incretin therapy. Our studies will be paralleled in a human clinical trial, a human cell culture model, and a mouse
diet-induced obesity model. GLP-1 analog therapy combined with an IL-6 blocking antibody will be used. Specific
Aim 1 is to (A) investigate IL-6 induction / downstream STAT3 signaling and AT browning upon incretin therapy
in prediabetic human patients; and (B) validate mice as a model to study incretin-induced IL-6 signaling as a
mediator of AT browning. Specific Aim 2 is to (A) investigate if GLP-1 analog effects on beige adipogenesis
depend on IL-6 signaling in human adipocyte progenitors; and (B) investigate if GLP-1 analog effects on beige
adipogenesis depend on IL-6 signaling in mice. We expect to discover that 1) GLP-1 analog signaling via GLP-
1R induces IL-6 secretion by leukocytes, and 2) GLP-1 analog therapy induces adipose tissue browning via both
direct GLP-1 / GLP-1R signaling and indirect incretin-induced IL-6 / IL-6R / STAT3 signaling. The results of this
novel study will give critical insights on the anti-obesity mechanisms of GLP-1 analogs and serve as the basis
for developing more targeted therapies for diabetes and obesity. Understanding the anti-diabetic IL-6 effects will
also be important for interpreting the results of IL-6 blockade, a therapeutic approach for patients with diabetes
and other inflammatory conditions, which may need to be re-considered.

## Key facts

- **NIH application ID:** 10015259
- **Project number:** 5R21DK122234-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Absalon Dennis Gutierrez
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,792
- **Award type:** 5
- **Project period:** 2019-09-10 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015259

## Citation

> US National Institutes of Health, RePORTER application 10015259, GLP-1 Therapy:  The Role of IL-6 Signaling and Adipose Tissue Remodeling in Metabolic Response (5R21DK122234-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10015259. Licensed CC0.

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