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 9

Improved hepatic insulin sensitivity in AFasKO mice.

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Improved hepatic insulin sensitivity in AFasKO mice. (A) Lysates were im...
(A) Lysates were immunoblotted with anti–phospho-IRS1 (Ser307) and total IRS1 antibody. Expression levels of pSer307 are normalized to expression of total IRS1. Results are mean ± SEM of 4 mice and expressed relative to WT. *P < 0.05 (Student’s t test). (B) Hepatic glucose production was calculated in the basal period and in response to insulin infusion during the hyperinsulinemic-euglycemic clamp study. Results are mean ± SEM of 3–4 animals per group and expressed relative to basal hepatic glucose production. **P < 0.01 (Student’s t test). (C) 3T3-L1 adipocytes were incubated with or without FasL for 12 hours, and subsequently, supernatant was collected for 24 hours. Hepatoma cells (Fao) were incubated with the conditioned medium for 24 hours. Total cell lysates were prepared and resolved by LDS-PAGE and immunoblotted with anti–phospho-Akt or Akt antibody. Results are mean ± SEM of 7–9 independent experiments. **P < 0.01 (ANOVA).