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.
Highlights
Obese people are prone to type 2 diabetes, arising from relative insulin deficiency combined with insulin resistance
We previously found that Fas ablation in adipocytes reduced adipose tissue inflammation and hepatic insulin resistance in high fat‐fed mice, highlighting a role for Fas in the disturbed adipocyte–hepatocyte communication observed in obesity (Wueest et al, 2010b)
Fas expression in circulating monocytes correlates with insulin resistance and type 2 diabetes in obese patients To unravel whether obesity has an impact on myeloid Fas expression, mRNA levels were determined in circulating monocytes of lean and obese human subjects (body mass index (BMI): 21.4 Æ 0.5 kg/m2 in lean vs. 45.9 Æ 1.1 kg/m2 in obese subjects, p < 0.0001)
Summary
Obese people are prone to type 2 diabetes, arising from relative insulin deficiency combined with insulin resistance. The latter is defined as impaired ability of insulin to promote glucose uptake into skeletal muscle and adipose tissue as well as to inhibit hepatic glucose production.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
