Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals

• DOI: 10.1016/j.cmet.2016.08.005
• Publication Date: 2016-09-13T20:33:51Z
• Authors: Yi Zhu; Yong Gao; Caroline Tao; Mengle Shao; Shangang Zhao; Wei Huang; Ting Yao; Joshua A. Johnson; Tiemin Liu; Aaron M. Cypess; Olga Gupta; William L. Holland; Rana K. Gupta; David C. Spray; Herbert B. Tanowitz; Lei Cao; Matthew D. Lynes; Yu-Hua Tseng; Joel K. Elmquist; Kevin W. Williams; Hua V. Lin; Philipp E. Scherer
• Keywords: Neurons; 0301 basic medicine; Sympathetic Nervous System; Adipose Tissue, White; Gap Junctions; Adipose Tissue, Beige; Adaptation, Physiological; Denervation; Models, Biological; Cold Temperature; Mice, Inbred C57BL; 03 medical and health sciences; Adipose Tissue, Brown; Connexin 43; Animals; Glycyrrhetinic Acid; Promoter Regions, Genetic; Gene Deletion; Uncoupling Protein 1; Signal Transduction

"Beige" adipocytes reside in white adipose tissue (WAT) and dissipate energy as heat. Several studies have shown that cold temperature can activate pro-opiomelanocortin-expressing (POMC) neurons and increase sympathetic neuronal tone to regulate WAT beiging. WAT, however, is traditionally known to be sparsely innervated. Details regarding the neuronal innervation and, more importantly, the propagation of the signal within the population of "beige" adipocytes are sparse. Here, we demonstrate that beige adipocytes display an increased cell-to-cell coupling via connexin 43 (Cx43) gap junction channels. Blocking of Cx43 channels by 18α-glycyrrhetinic acid decreases POMC-activation-induced adipose tissue beiging. Adipocyte-specific deletion of Cx43 reduces WAT beiging to a level similar to that observed in denervated fat pads. In contrast, overexpression of Cx43 is sufficient to promote beiging even with mild cold stimuli. These data reveal the importance of cell-to-cell communication, effective in cold-induced WAT beiging, for the propagation of limited neuronal inputs in adipose tissue.