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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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 7

Increased secretion of immunoattractant cytokines and higher macrophage adherence in FasL-treated 3T3-L1 adipocytes.

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Increased secretion of immunoattractant cytokines and higher macrophage ...
(A) Fas ligation increases expression of proinflammatory cytokines in 3T3-L1 adipocytes. Mature 3T3-L1 adipocytes were incubated in the presence or absence of 2 ng/ml FasL for 12 hours. Medium was removed, and cells were incubated with KREBS buffer. Cytokine levels were then determined in the supernatant. Shown are results normalized to untreated cells. Results represent mean ± SEM of 4–5 independent experiments. *P < 0.05 (1-sample t test). (B) Mature 3T3-L1 adipocytes were incubated in the presence or absence (control [Co]) of 2 ng/ml FasL for 12 hours. Thereafter, adipocytes were incubated with 3H-labeled macrophages for 1 hour at 37°C. Cells were washed and lysed (0.05N NaOH). Finally, radioactivity of lysates was determined by a beta counter. Results represent mean ± SEM of 7 independent experiments. *P < 0.05 (1-sample t test).