Obesity is a leading global health concern and a major risk factor for type-2 diabetes. Thus, identifying mechanisms linking obesity to insulin resistance is of great importance. Chronic low-grade inflammation of the adipose tissue (AT) observed in obesity has been shown as an important pathophysiological link between obesity and the development of systemic insulin resistance, by various mechanisms. Gap junction (GJ) intercellular-communication, primarily composed of connexin- (Cx) 43, has been recently reported to have immunomodulatory roles in various tissues, and increased Cx43 expression and GJ activity have been implicated in the response of various tissues to chronic stress conditions. We have therefore aimed to study the role of Cx43 in shaping the AT adaptive or maladaptive response to these cellular insults of obesity. In a diet-induced obesity mouse model we demonstrated an increase in Cx43 expression in the intact AT, which could be primarily attributed to increased Cx43 expression in adipocytes. In high fat diet-fed adipocyte-specific Cx43 knock-out mice (AdCx43KO) , we observed increased infiltration of macrophages to the AT as compared to wild-type (WT) mice. This was accompanied by morphologic changes in the AT, with increased variability in adipocyte size. While AdCx43KO mice did not significantly differ from WT mice in body weight, adiposity or food intake, the AdCx43KO mice demonstrated reduced whole-body insulin sensitivity assessed by insulin tolerance test. Mechanistically, we observed that adipocytes can interact directly with neighboring adipocytes as well as with macrophages via Cx43-composed gap junctions, an interaction that is likely to be key in attenuation of the tissue inflammatory response. Our results suggest an immunomodulatory and metabolic role for adipocyte-Cx43 in obesity.
S.Ron: None. I.Ron: None. M.Rathaus: None. R.Livne: None. A.Tirosh: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Novo Nordisk, Sanofi, Consultant; Bayer AG, DreaMed Diabetes, Ltd., Research Support; Medtronic, Speaker's Bureau; Eli Lilly and Company.
Israel Science Foundation (922/17)