# Enhancing metabolic action of FGF21 through adipocyte Connexin43 gap junction channels

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $437,829

## Abstract

PROJECT SUMMARY/ABSTRACT
Obese and Type 2 diabetic (T2D) patients still need therapeutics with enhanced efficacy and improved safety.
Adipose tissue is a promising target for treating obesity and T2D. However, pharmacological agents usually fail
to effectively engage adipocytes due to their extraordinary size and insufficient vascularization, especially in
obese subjects. Our previous work suggests connexin43 (Cx43) gap junctions are activated and induced to
connect neighboring adipocytes to share limited sympathetic neuronal inputs among multiple cells. Our recent
publication reveals that danegaptide, a Connexin43 gap junction channel activator, significantly enhances
adipocyte coupling and the metabolic efficacy of fibroblast growth factor 21 (FGF21). Preliminary work showed
adipocyte-specific Cx43 overexpression enhanced FGF21’s efficacy on weight loss and improvement in
metabolism, largely recapitulating the danegaptide’s potentiation effect on FGF21. Based on our preliminary
data and literature, we propose a hierarchical and coordinated “ignition-combustion” model by which FGF21
engages the brain and adipose tissue to regulate systemic metabolism. Enhancing Cx43 gap junctions
between adipocytes facilitates the dissemination of FGF21-activated sympathetic signals from the brain and
adipocytes’ autonomous FGF21 signals. Due to low Klb expression in the brain, we postulate the brain usually
receives sufficient FGF21 inputs. In contrast, adipose tissue, especially from obese subjects, is insufficiently
innervated and refractory to FGF21-stimulated cellular response. With several new mouse models and FGF21
analogs developed, we propose to (A) understand the importance of the adipocyte Cx43’s gap junction
channel function in enhancing FGF21’s metabolic benefits, (B) test the “ignition-combustion” model, and the
importance of enhancing “combustion” in the adipose tissue in improving FGF21’s efficacy. We will also test
(C) an orthogonal, step-by-step approach to achieving Cx43 gap junction and FGF21 dual agonism in the
adipose tissue. Altogether, these studies will provide novel insights into how FGF21 coordinates multiple
organs to regulate energy expenditure and how targeting adipose tissue gap junctions can enhance adipose
tissue pharmaceutical engagement. In this process, we will also generate several new FGF21 analogs that can
be tested as potential therapeutics for obesity and T2D.

## Key facts

- **NIH application ID:** 10917213
- **Project number:** 5R01DK136619-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Yi Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,829
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917213

## Citation

> US National Institutes of Health, RePORTER application 10917213, Enhancing metabolic action of FGF21 through adipocyte Connexin43 gap junction channels (5R01DK136619-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10917213. Licensed CC0.

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