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

Cell Rep Med. 2022 Nov 15;3(11):100813. doi: 10.1016/j.xcrm.2022.100813.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes* / metabolism
  • Animals
  • Glucagon-Like Peptide 1* / analogs & derivatives
  • Humans
  • Interleukin-6* / metabolism
  • Liraglutide* / pharmacology
  • Mice
  • Signal Transduction
  • Thermogenesis*

Substances

  • Interleukin-6
  • Liraglutide
  • Glucagon-Like Peptide 1