Fas (CD95) expression in myeloid cells promotes obesity‐induced muscle insulin resistance

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, bl...

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Bibliographic Details
Published in:EMBO molecular medicine 2014-01, Vol.6 (1), p.43-56
Main 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
Format: Article
Language:English
Subjects:
Adipocytes
Adipose tissue
Adult
Aged
Animal models
Animals
Antibodies, Neutralizing - immunology
CD95 antigen
Cohort Studies
Cross-Sectional Studies
Cytokines
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - complications
Diabetes Mellitus, Type 2 - metabolism
fas Receptor - deficiency
fas Receptor - genetics
fas Receptor - metabolism
Female
Gastrointestinal surgery
Gene Expression Regulation
Glucose
Glucose tolerance
Homeostasis
Humans
Hypotheses
Inflammation
Insulin
Insulin Resistance
Intolerance
Lipopolysaccharides
Liver
Male
Metabolism
Mice
Mice, Inbred C57BL
Mice, Obese
Middle Aged
Monocytes
Monocytes - metabolism
Muscle, Skeletal - metabolism
Musculoskeletal system
Myeloid cells
Obesity
Obesity - complications
Obesity - metabolism
Pathogenesis
Preservation
Skeletal muscle
Tumor necrosis factor-α
Weight control
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Summary: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 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 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.
ISSN:1757-4676
1757-4684
DOI:10.1002/emmm.201302962