SEARCH

SEARCH BY CITATION

Keywords:

  • diabetes mellitus;
  • insulin resistance;
  • obesity

Abstract

Low-grade inflammation in adipose tissue and liver has been implicated in obesity-associated insulin resistance and type 2 diabetes. Yet, the contribution of inflammatory cells to the pathogenesis of skeletal muscle insulin resistance remains elusive. In a large cohort of obese human individuals, blood monocyte Fas (CD95) expression correlated with systemic and skeletal muscle insulin resistance. To test a causal role for myeloid cell Fas expression in the development of skeletal muscle insulin resistance, we generated myeloid/haematopoietic cell-specific Fas-depleted mice. Myeloid/haematopoietic Fas deficiency prevented the development of glucose intolerance in high fat-fed mice, in ob/ob mice, and in mice acutely challenged by LPS. In vivo, ex vivo and in vitro studies demonstrated preservation of muscle insulin responsiveness with no effect on adipose tissue or liver. Studies using neutralizing antibodies demonstrated a role for TNFα as mediator between myeloid Fas and skeletal muscle insulin resistance, supported by significant correlations between monocyte Fas expression and circulating TNFα in humans. In conclusion, our results demonstrate an unanticipated crosstalk between myeloid cells and skeletal muscle in the development of obesity-associated insulin resistance.

Synopsis

Thumbnail image of graphical abstract

Fas expression in circulating monocytes correlates with skeletal muscle insulin resistance in obese humans and loss of Fas in myeloid cells decreases the release of TNFα and thus protects mice from obesity-induced skeletal muscle insulin resistance.

  • Fas protein levels are increased in myeloid cells of obese and LPS-treated mice
  • Mice with myeloid-specific Fas-depletion are protected from obesity-induced skeletal muscle insulin resistance
  • LPS-induced TNFα production in myeloid cells is mediated by Fas
  • In humans, muscle insulin sensitivity is negatively correlated with monocytic Fas expression