Inter-cellular transmission of hepatic ER stress in obesity disrupts systemic metabolism

Moran Rathaus ¹ Neri Minsky ¹ Idit Ron ¹ Rinat Livne ¹ Sophie T. Ron ^1,5 Gurol Tuncman ² Ediz S. Calay ² Abdullah Yalcin ^2,3 Grace Y. Lee ² Gökhan S. Hotamisligil ^2,4 Amir Tirosh ^1,5

¹The Dalia and David Arabov Endocrinology and Diabetes Research Center, The Institute of Endocrinology, Sheba Medical Center, Israel
²Sabri ÜLker Center and Department of Genetics and Complex Diseases, Harvard T.h. Chan School of Public Health, USA
³Department of Medical Biology, Aydin Adnan Menderes University Medical School, Turkey
⁴Broad Institute, of MIT and Harvard, USA
⁵Sackler Faculty of Medicine, Tel Aviv University, Israel

Cellular events linking ER stress and insulin resistance are well characterized processes, however how an organ coordinates its adaptive response to stress and the role of communication between its cellular constituents remains unclear. Increased gap junction (GJ) intercellular communication, primarily composed of connexin (Cx)43, plays a key role in the maladaptive tissue response to various stresses and implicated in the pathogenesis of diseases characterized by chronic low-grade inflammation and ER stress.

Here we demonstrate that in hepatocytes, ER stress results in increased expression of Cx43 and increased GJ mediated cell-cell coupling. Co-culture of ER stressed-donor cells with ER stress-naive-recipient cells resulted in inter-cellular transmission of ER stress signals and activation of the unfolded protein response. This response resulted in chaperon consumption and impaired folding capacity of the recipient cells. The propagation of ER stress required cell-cell contact, and genetic suppression of Cx43 prevented the transmission of ER stress. We also observed that diet induced obesity resulted in hepatic ER stress and upregulation of Cx43 in the liver. Hepatocytes from HFD-fed mice were able to transmit ER stress to intact hepatocytes from lean mice in a Cx43-dependent manner. Mice lacking Cx43 specifically in the liver were protected from HFD induced liver ER stress, insulin resistance, glucose intolerance and hepatosteatosis.

Our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling may cause tissue propagation of ER stress. This novel maladaptive response to metabolic stress exacerbates ER dysfunction in the liver, promoting hepatosteatosis and impairs whole-body glucose metabolism.