Activating connexin43 gap junctions primes adipose tissue for therapeutic intervention

Authors: ZHU, YI - Children'S Nutrition Research Center (CNRC); LI, NA - University Of Texas Southwestern Medical Center; HUANG, MINGYANG - Children'S Nutrition Research Center (CNRC); CHEN, XI - Children'S Nutrition Research Center (CNRC); AN, YU - University Of Texas Southwestern Medical Center; LI, JIANPING - University Of Texas Southwestern Medical Center; ZHAO, SHANGANG - University Of Texas Southwestern Medical Center; FUNCKE, JAN-BERND - University Of Texas Southwestern Medical Center; CAO, JIANHONG - University Of Texas Southwestern Medical Center; HE, ZHENYAN - University Of Texas Southwestern Medical Center; ZHU, QINGZHANG - University Of Texas Southwestern Medical Center; ZHANG, ZHUZHEN - University Of Texas Southwestern Medical Center; WANG, ZHAO - University Of Texas Southwestern Medical Center; XU, LIN - University Of Texas Southwestern Medical Center; WILLIAMS, KEVIN - University Of Texas Southwestern Medical Center; LI, CHIEN - Novo Nordisk, Inc; GROVE, KEVIN - Novo Nordisk, Inc; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center

Submitted to: Acta Pharmaceutica Sinica B
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/8/2022
Publication Date: 7/1/2022
Citation: Zhu, Y., Li, N., Huang, M., Chen, X., An, Y.A., Li, J., Zhao, S., Funcke, J., Cao, J., He, Z., Zhu, Q., Zhang, Z., Wang, Z.V., Xu, L., Williams, K.W., Li, C., Grove, K., Scherer, P.E. 2022. Activating connexin43 gap junctions primes adipose tissue for therapeutic intervention. Acta Pharmaceutica Sinica B. 12(7):3063-3072. https://doi.org/10.1016/j.apsb.2022.02.020.
DOI: https://doi.org/10.1016/j.apsb.2022.02.020

Interpretive Summary: Obesity is a major risk factor for many chronic diseases, including the most common comorbiditydtype two diabetes (T2D). Fat tissue is a promising target for treating obesity and metabolic diseases. This paper is based on our 2016 Cell Metabolism report that Connexin43 gap junctions were upregulated in adipocytes to disseminate limited neuronal inputs to the fat tissue. This paper demonstrates that coupling adipocytes Connexins enhances pharmaceutical agents targeting adipocytes. Future efforts will need to be targeted toward a better understanding of the identity of molecules that pass through the gap junctions and how they effectuate the enhanced metabolic benefits.

Technical 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 Beta3-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 via 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.