Gutierrez 2022 Cell Rep Med

Gutierrez AD, Gao Z, Hamidi V, Zhu L, Saint Andre KB, Riggs K, Ruscheinsky M, Wang H, Yu Y, Miller C 3rd, Vasquez H, Taegtmeyer H, Kolonin MG (2022) Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes.

» Cell Rep Med 3:100813. PMID: 36384099 Open Access

Gutierrez AD, Gao Z, Hamidi V, Zhu L, Saint Andre KB, Riggs K, Ruscheinsky M, Wang H, Yu Y, Miller C 3rd, Vasquez H, Taegtmeyer H, Kolonin MG (2022) Cell Rep Med

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.

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2022-11