Visual Abstract

Mechanisms underlying antidiabetic effects of incretins remain incompletely understood. We have discovered that GLP-1 analogs increase IL-6 secretion from leukocytes and, hence, IL-6 plasma levels in obese humans and mice. Based on the observation that IL-6 induces STAT3 phosphorylation in preadipocytes, we hypothesized that incretins may regulate adipose tissue (AT) function by IL-6-dependent control of white vs. beige adipogenesis. Here, we show that IL-6 promotes liraglutide-induced increase in UCP-1 expression in mouse preadipocytes. Two weeks of liraglutide therapy in mice raised on high-fat diet (HFD) resulted in a reduced adiposity, increased AT beiging, increased cold tolerance and better glucose control, compared to untreated mice. Importantly, simultaneous administration of an antibody blocking IL-6 inhibited the antidiabetic effects of liraglutide. Our data indicate that GLP-1 analogs suppress obesity and diabetes in part through an IL-6-dependent induction of adipocyte beiging.

graphic
View largeDownload slide
Disclosure

A. D. Gutierrez: None. Z. Gao: None. V. Hamidi: None. M. Kolonin: None.

Funding

National Institutes of Health (5R21DK122234 to A.D.G.)

© 2021 by the American Diabetes Association
2021
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.