Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes.

Autor:	Gutierrez AD; Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, The University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: absalon.d.gutierrez@uth.tmc.edu., Gao Z; The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA., Hamidi V; Department of Medicine, Division of Endocrinology, University of California San Diego, La Jolla, CA 92093, USA., Zhu L; Department of Internal Medicine, Division of Clinical and Translational Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA., Saint Andre KB; Department of Medicine, Division of Endocrinology, Houston Methodist, Houston, TX 77030, USA., Riggs K; Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern, Dallas, TX 75225, USA., Ruscheinsky M; Department of Pathology, University of Texas Southwestern, Dallas, TX 75390, USA., Wang H; The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA., Yu Y; The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA., Miller C 3rd; Department of Cardiothoracic and Vascular Surgery, The University of Texas Health Science Center, Houston, TX 77030, USA., Vasquez H; Department of Internal Medicine, Division of Cardiovascular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA., Taegtmeyer H; Department of Internal Medicine, Division of Cardiovascular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA., Kolonin MG; The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: mikhail.g.kolonin@uth.tmc.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2022 Nov 15; Vol. 3 (11), pp. 100813.
DOI:	10.1016/j.xcrm.2022.100813
Abstrakt:	Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced increase in thermogenesis and glucose utilization. We show that adipose IL-6R knockout mice still display liraglutide-induced weight loss but lack thermogenic adipocyte browning and metabolism activation. We conclude that the anti-diabetic effects of GLP1 analogs are mediated by transient upregulation of IL-6, which activates canonical IL-6R signaling and thermogenesis. Competing Interests: Declaration of interests A.D.G. previously served on the Speakers’ Bureau for AstraZeneca Pharmaceuticals. AstraZeneca provided study medications for the randomized controlled trial but was not involved in study design, data analyses, or manuscript preparation. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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