Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals.
"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.
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
Yi
Y
Zhu
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; National Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100005, People's Republic of China.
Yong
Y
Gao
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Caroline
C
Tao
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mengle
M
Shao
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Shangang
S
Zhao
Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Wei
W
Huang
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, 76 West Yanta Road, Xi'an, Shaanxi 710061, People's Republic of China.
Ting
T
Yao
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Joshua A
JA
Johnson
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Tiemin
T
Liu
Translational Physiology Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
Aaron M
AM
Cypess
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Olga
O
Gupta
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
William L
WL
Holland
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Rana K
RK
Gupta
Departments of Neuroscience and Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
David C
DC
Spray
Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Herbert B
HB
Tanowitz
Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Lei
L
Cao
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Matthew D
MD
Lynes
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Yu-Hua
YH
Tseng
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Joel K
JK
Elmquist
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kevin W
KW
Williams
Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
Hua V
HV
Lin
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: philipp.scherer@utsouthwestern.edu.
Philipp E
PE
Scherer
D000222:Adaptation, Physiological / Q000187:drug effects; D000069796:Adipose Tissue, Beige / Q000187:drug effects / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D000818:Animals; D003080:Cold Temperature; D018031:Connexin 43 / Q000378:metabolism*; D003714:Denervation; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000473:pathology; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
D018031:Connexin 43; D000071256:Uncoupling Protein 1; C119129:18alpha-glycyrrhetinic acid; D006034:Glycyrrhetinic Acid
beiging; connexin 43; sympathetic signal; white adipose tissue