Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice
Stephan Wueest, … , Marc Y. Donath, Daniel Konrad
Stephan Wueest, … , Marc Y. Donath, Daniel Konrad
Published December 1, 2009
Citation Information: J Clin Invest. 2010;120(1):191-202. https://doi.org/10.1172/JCI38388.
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Research Article Metabolism

Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice

Abstract

Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting death-promoting effects, the death receptor Fas (also known as CD95) can activate inflammatory pathways in several cell lines and tissues, although little is known about the metabolic consequence of Fas activation in adipose tissue. We therefore sought to investigate the contribution of Fas in adipocytes to obesity-associated metabolic dysregulation. Fas expression was markedly increased in the adipocytes of common genetic and diet-induced mouse models of obesity and insulin resistance, as well as in the adipose tissue of obese and type 2 diabetic patients. Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were protected from deterioration of glucose homeostasis induced by high-fat diet (HFD). Adipocytes in AFasKO mice were more insulin sensitive than those in wild-type mice, and mRNA levels of proinflammatory factors were reduced in white adipose tissue. Moreover, AFasKO mice were protected against hepatic steatosis and were more insulin sensitive, both at the whole-body level and in the liver. Thus, Fas in adipocytes contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity and may constitute a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

Authors

Stephan Wueest, Reto A. Rapold, Desiree M. Schumann, Julia M. Rytka, Anita Schildknecht, Ori Nov, Alexander V. Chervonsky, Assaf Rudich, Eugen J. Schoenle, Marc Y. Donath, Daniel Konrad

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Figure 2

Fas-def mice are protected from HFD-induced changes in adipose tissue and glucose homeostasis.

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Fas-def mice are protected from HFD-induced changes in adipose tissue an...
(A) Weight gain was analyzed in HFD-fed WT and Fas-def mice. Results are mean ± SEM of 10 animals per group. (B) Perigonadal fat pads were harvested and weighed. Results are expressed relative to total body weight and represent mean ± SEM of 10–15 mice group. *P < 0.05 (Student’s t test). (C) Left: Relative size distribution of adipocyte diameter after 6 weeks of HFD. Results represent mean ± SEM of 6 mice per group. Right: Mean adipocyte diameter of chow- or HFD-fed Fas-def and WT mice. Results represent mean ± SEM of 6 mice per group. *P < 0.05 (Student’s t test). (D) Intraperitoneal glucose tolerance tests in WT (left) and Fas-def (right) mice. Results are mean ± SEM of 12–18 animals per group. *P < 0.05, **P < 0.01 (Student’s t test). (E) Fasting insulin levels were determined in WT (left) and Fas-def (right) mice after 8 hours of food withdrawal. Results are mean ± SEM of 4–5 animals per group. *P < 0.05 (Student’s t test). (F) 14C-d-glucose incorporation into isolated adipocytes from chow- and HFD-fed mice was determined in the absence or presence of insulin. Left: Fold glucose incorporation in WT mice. Right: Fold glucose incorporation in Fas-def mice. Results represent mean ± SEM of 6 experiments. **P < 0.01 (Student’s t test).