Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism
Authors: Sophie Ron
Ana Paula Arruda
Amit Tirosh
Neri Minsky
Rinat Livne
Yankun G Lee
Idit Ron
Abdullah Yalcin
Gurol Tuncman
Ediz S Calay
Moran Rathaus
Gökhan S Hotamisligil
Amir Tirosh
Journal: Cell Metabolism (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: connexin 43; diabetes; endoplasmic reticulum stress; gap junctions; insulin resistance
Affiliations: Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Harvard Medical School, Boston, MA 02115, USA. Electronic address: ., Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, 52621 Tel-HaShomer, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Adnan Menderes Üniversitesi Medical School, Department of Medical Biology, 09100 Aydin, Turkey., Sabri Ülker Center for Metabolic Research, Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: .

Abstract:  Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism. 

Retracted: No

PubPeer comments:
 Figure 2B: Could authors check please? (Purple) ![file] , 
 Dear reader, Thank you very much for pointing this out. You are correct. Unfortunately, during preparation of this panel, the Tg-treated UPRE_mCh image, used as a template for the alignments of all other images, accidently left in the place of the Tm-treated ERSE_mCh, masking the correct image. As such, it appears in the figure as if there are two identical images. We deeply regret this unfortunate error, and contacted the Journal with a request to publish the corrected version of the figure as erratum. I would like to thank you again for raising our attention for this error. Amir Tirosh ,