1. Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes.
- Author
-
Zhu, Liang, Saint Andre, Karla, Riggs, Kayla, Ruscheinsky, Monika, Wang, Hongyu, Yu, Yongmei, Miller, Charles, Vasquez, Hernan, Taegtmeyer, Heinrich, Kolonin, Mikhail, Gutierrez, Absalon, Gao, Zhanguo, and Hamidi, Vala
- Subjects
GLP1 ,brown adipocyte ,diabetes ,exenatide ,incretin ,interleukin-6 ,liraglutide ,Animals ,Humans ,Mice ,Adipocytes ,Interleukin-6 ,Liraglutide ,Signal Transduction ,Thermogenesis ,Glucagon-Like Peptide 1 - 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.
- Published
- 2022