Fas (CD95) expression in myeloid cells promotes obesity‐induced muscle insulin resistance. Issue 1 (6th November 2013)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 1(2014:Jan.)
• Page Start: 43
• Page End: 56
• Publication Date: 2013-11-06
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201302962
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201302962-abs-0001"> <title>Abstract</title> <p>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 <italic>Fas</italic> (<italic>CD95</italic>) 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 <italic>ob</italic>/<italic>ob</italic> mice, and in mice acutely challenged by LPS. <italic>In vivo</italic>, <italic> ex vivo</italic> and <italic>in vitro</italic> 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 <italic>Fas</italic> 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.</p> </abstract>