Luoyo

Research article

Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice
Stephan Wueest,1,2 Reto A. Rapold,1,2 Desiree M. Schumann,3 Julia M. Rytka,1,2 Anita Schildknecht,4 Ori Nov,5 Alexander V. Chervonsky,6 Assaf Rudich,5 Eugen J. Schoenle,1 Marc Y. Donath,2,3 and Daniel Konrad1,2
1Division

of Pediatric Endocrinology andDiabetology, University Children’s Hospital, Zurich, Switzerland. 2Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. 3Clinic of Endocrinology and Diabetes and 4Institute of Experimental Immunology, University Hospital Zurich, Zurich, Switzerland. 5Department of Clinical Biochemistry and S. Daniel Centre for Health and Nutrition, Ben-Gurion University,Beer-Sheva, Israel. 6Department of Pathology, University of Chicago, Chicago, Illinois, USA.

Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting deathpromoting 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 ofFas 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 deficiencyeither 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 protectedagainst 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.
IntroductionWhite adipose tissue (WAT) has been recognized as an important  endocrine organ secreting different hormone-like factors (adipokines), FFAs, and cytokines, thereby regulating metabolism locally  and systemically (1). In obesity, excess adipose tissue accumulation is accompanied by local inflammation, characterized by infiltration of inflammatory cells (2) and by elevated production of proinflammatory cytokines, jointly activating inflammatory pathways  in adipocytes. It is proposed that the consequent alteration in the  composition of secreted products from adipocytes contributes  to both local and systemic insulin resistance (3–5). Particularly,  liver insulin sensitivity can be impaired by obesity-induced alterations in adipokine secretion and by elevation in fat tissue–derived  cytokines and fatty acids (6–9).Fas (CD95), a member of the TNF receptor family, plays an  important role in the regulation of programmed cell death (apoptosis). FasL binding to Fas assembles the death-inducing signaling  complex (DISC). In turn, DISC formation leads to the activation  of caspase-8 and caspase-3 and finally to apoptosis. However, like  TNF-α, Fas activation can also induce non-apoptotic signaling  pathways (10–12). For example, in different cell lines and tissues, Fas activation was shown to induce secretion of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8 (KC), and MCP-1  (13–17), rendering it a potential key component of the inflammatory response. Although Fas was shown to be expressed in preadipocytes and adipocytes (18), little is known about non-apoptotic 
Conflict of...