Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention  

作　　者：Yi Zhu Na Li Mingyang Huang Xi Chen Yu AAn Jianping Li Shangang Zhao Jan-Bernd Funck Jianhong Cao Zhenyan He Qingzhang Zhu Zhuzhen Zhang Zhao VWang Lin Xu Kevin W.Williams Chien Li Kevin Grove Philipp E.Scherer 

机构地区：[1]Touchstone Diabetes Center,Department of Internal Medicine,the University of Texas Southwestern Medical Center at Dallas,Dallas,TX 75390,USA [2]Division of Cardiology,Department of Internal Medicine,the University of Texas Southwestern Medical Center at Dallas,Dallas,TX 75390,USA [3]Division of Hypothalamic Research,Department of Internal Medicine,the University of Texas Southwestern Medical Center at Dallas,Dallas,TX 75390,USA [4]Quantitative Biomedical Research Center,Department of Population and Data Sciences,the University of Texas Southwestern Medical Center at Dallas,Dallas,TX 75390,USA [5]Department of Pediatrics,the University of Texas Southwestern Medical Center at Dallas,Dallas,TX 75390,USA [6]Novo Nordisk Research Center,Seattle,WA 98109,USA [7]Children’s Nutrition Research Center,Department of Pediatrics,Baylor College of Medicine,Houston,TX 77030,USA [8]Department of Cell Biology,the University of Texas Southwestern Medical Center at Dallas,Dallas,TX 75390,USA

出　　处：《Acta Pharmaceutica Sinica B》2022年第7期3063-3072,共10页药学学报（英文版）

基　　金：supported in part by a research grant from Novo Nordsik(USA,to Philipp E.Scherer);by NIH Grants(USA)R01-DK55758,R01-DK099110,R01-DK127274,R01DK131537 and P01-AG051459 to Philipp E.Scherer,NIH Grant R00-DK114498;NIH Grant K99-AG068239 to Shangang Zhao;NIH Grant K01-DK125447 to Yu A.An;NIH grants R01 DK119169 and P01 DK119130-5830 to Kevin W.Williams;USDA ARS(cooperative agreement 309251000-062)to Yi Zhu;AHA Career Development Award 855170(USA)to Qingzhang Zhu。

摘　　要：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 theβ_(3)-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.

关 键 词：GJA1 Adipose tissue Gap junction CONNEXIN43 FGF21 β3-Adrenergic receptor agonist OBESITY Type 2 diabetes 

分 类 号：R914[医药卫生—药物化学]