Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice

Nat Metab. 2021 Apr;3(4):496-512. doi: 10.1038/s42255-021-00371-1. Epub 2021 Apr 15.

Abstract

Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects*
  • Adipose Tissue, Brown / physiology
  • Animals
  • Cyclin-Dependent Kinase 5 / metabolism
  • Diet
  • Diet, High-Fat
  • Digoxin / pharmacology
  • Energy Metabolism / physiology
  • Feces / chemistry
  • Gene Deletion
  • Interleukin-17 / antagonists & inhibitors*
  • Metabolic Diseases / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Obesity / prevention & control*
  • Overnutrition
  • PPAR gamma / metabolism
  • Phosphorylation
  • Thermogenesis / physiology

Substances

  • Il17a protein, mouse
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • PPAR gamma
  • Rorc protein, mouse
  • Digoxin
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, mouse