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.
View: Text | PDF
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

×

Figure 1

Fas expression is increased in adipocytes isolated from insulin-resistant mice and in adipose tissue of obese and diabetic patients.

Options: View larger image (or click on image) Download as PowerPoint
Fas expression is increased in adipocytes isolated from insulin-resistan...
(A) Total cell lysates were prepared from isolated perigonadal adipocytes harvested from db/db, ob/ob, and WT control mice. Lysates were resolved by LDS-PAGE and immunoblotted with anti-Fas or anti-actin antibody. Results are mean ± SEM of 3 mice per group and normalized to actin expression. *P < 0.05 (Student’s t test). (B) Total cell lysates were prepared from isolated adipocytes of perigonadal fat pads of chow-fed and HFD-fed (8 weeks of HFD) mice. Lysates were resolved by LDS-PAGE and immunoblotted with anti-Fas or anti-actin antibody. Results are mean ± SEM of 3 mice per group and normalized to actin expression. *P < 0.05 (1-sample t test). (C) Total RNA was extracted from perigonadal fat pads, and quantitative RT-PCR was performed. The level of mRNA expression was normalized to 18S RNA. Results represent mean ± SEM of 3 animals per group. *P < 0.05, **P < 0.01 (Student’s t test). (D) Tissue lysates from subcutaneous fat biopsies of lean, obese, and diabetic patients were prepared and immunoblotted with anti-Fas or anti-actin antibody. Results are mean ± SEM of 5–10 patients per group and normalized to actin expression. *P < 0.05 (ANOVA).