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

Absalon D. Gutierrez; Zhanguo Gao; Vala Hamidi; Liang Zhu; Karla Bermudez Saint Andre; Kayla Riggs; Monika Ruscheinsky; Hongyu Wang; Yongmei Yu; Charles Miller; Hernan Vasquez; Heinrich Taegtmeyer; Mikhail G. Kolonin

doi:10.1016/j.xcrm.2022.100813

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

Absalon D. Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G. Kolonin

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14 Scopus citations

Abstract

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.

Original language	English (US)
Article number	100813
Journal	Cell Reports Medicine
Volume	3
Issue number	11
DOIs	https://doi.org/10.1016/j.xcrm.2022.100813
State	Published - Nov 15 2022

Keywords

GLP1
brown adipocyte
diabetes
exenatide
incretin
interleukin-6
liraglutide

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.xcrm.2022.100813

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Gutierrez, A. D., Gao, Z., Hamidi, V., Zhu, L., Saint Andre, K. B., Riggs, K., Ruscheinsky, M., Wang, H., Yu, Y., Miller, C., Vasquez, H., Taegtmeyer, H., & Kolonin, M. G. (2022). Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes. Cell Reports Medicine, 3(11), Article 100813. https://doi.org/10.1016/j.xcrm.2022.100813

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title = "Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes",

abstract = "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.",

keywords = "GLP1, brown adipocyte, diabetes, exenatide, incretin, interleukin-6, liraglutide",

author = "Gutierrez, {Absalon D.} and Zhanguo Gao and Vala Hamidi and Liang Zhu and {Saint Andre}, {Karla Bermudez} and Kayla Riggs and Monika Ruscheinsky and Hongyu Wang and Yongmei Yu and Charles Miller and Hernan Vasquez and Heinrich Taegtmeyer and Kolonin, {Mikhail G.}",

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doi = "10.1016/j.xcrm.2022.100813",

language = "English (US)",

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T1 - Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes

AU - Gutierrez, Absalon D.

AU - Gao, Zhanguo

AU - Hamidi, Vala

AU - Zhu, Liang

AU - Saint Andre, Karla Bermudez

AU - Riggs, Kayla

AU - Ruscheinsky, Monika

AU - Wang, Hongyu

AU - Yu, Yongmei

AU - Miller, Charles

AU - Vasquez, Hernan

AU - Taegtmeyer, Heinrich

AU - Kolonin, Mikhail G.

PY - 2022/11/15

Y1 - 2022/11/15

N2 - 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.

AB - 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.

KW - GLP1

KW - brown adipocyte

KW - diabetes

KW - exenatide

KW - incretin

KW - interleukin-6

KW - liraglutide

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ER -

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

Abstract

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