Activating Connexin43 Gap Junctions Primes Adipose Tissue for Therapeutic Intervention

Overview

Journal Acta Pharm Sin B

Publisher Elsevier

Specialty Pharmacology

Date 2022 Jul 22

PMID 35865093

Authors

Yi Zhu

Na Li

Mingyang Huang

Xi Chen

Yu A An

Jianping Li

Shangang Zhao

Jan-Bernd Funcke

Jianhong Cao

Zhenyan He

Qingzhang Zhu

Zhuzhen Zhang

Zhao V Wang

Lin Xu

Kevin W Williams

Chien Li

Kevin Grove

Philipp E Scherer

Affiliations

Soon will be listed here.

Abstract

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the -adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

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