Open AccessFas ( CD 95) expression in myeloid cells promotes obesity‐induced muscle insulin resistance
Author(s) -
Wueest Stephan,
Mueller Rouven,
Blüher Matthias,
Item Flurin,
Chin Annie S H,
Wiedemann Michael S F,
Takizawa Hitoshi,
Kovtonyuk Larisa,
Chervonsky Alexander V,
Schoenle Eugen J,
Manz Markus G,
Konrad Daniel
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201302962
Subject(s) - insulin resistance , medicine , endocrinology , myeloid , skeletal muscle , adipose tissue , haematopoiesis , monocyte , inflammation , biology , insulin , stem cell , microbiology and biotechnology
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 ( CD 95 ) 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 TNF α as mediator between myeloid Fas and skeletal muscle insulin resistance, supported by significant correlations between monocyte Fas expression and circulating TNF α in humans. In conclusion, our results demonstrate an unanticipated crosstalk between myeloid cells and skeletal muscle in the development of obesity‐associated insulin resistance.