Fas (CD95) expression in adipocytes contributes to diet-induced obesity

Stephan Wueest; Chiara Scaffidi; Pim P van Krieken; Nils K Konrad; Christian Koch; Michael S F Wiedemann; Anne Goergen; Marcela Borsigova; Ioannis G Lempesis; Jonas Fullin; Konstantinos N Manolopoulos; Steffen Böttcher; Gijs H Goossens; Matthias Blüher; Daniel Konrad

doi:10.1002/oby.24092

Fas (CD95) expression in adipocytes contributes to diet-induced obesity

Obesity (Silver Spring). 2024 Jul 17. doi: 10.1002/oby.24092. Online ahead of print.

Authors

Stephan Wueest^{1

2}, Chiara Scaffidi^{1

2}, Pim P van Krieken^{1

2}, Nils K Konrad^{1

2

3}, Christian Koch³, Michael S F Wiedemann^{1

2}, Anne Goergen^{1

2}, Marcela Borsigova^{1

2}, Ioannis G Lempesis^{4

5

6}, Jonas Fullin³, Konstantinos N Manolopoulos^{5

6}, Steffen Böttcher³, Gijs H Goossens⁴, Matthias Blüher^{7

8}, Daniel Konrad^{1

2

9}

Affiliations

¹ Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland.
² Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland.
³ Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
⁴ Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands.
⁵ Institute of Metabolism and Systems Research (IMSR), College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
⁶ Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.
⁷ Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
⁸ Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
⁹ Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

PMID: 39020501
DOI: 10.1002/oby.24092

Abstract

Objective: Induction of browning in white adipose tissue (WAT) increases energy expenditure and may be an attractive target for the treatment of obesity. Since activation of Fas (CD95) induces pathways known to blunt expression of uncoupling protein 1 (UCP1), we hypothesized that Fas expression in adipocytes inhibits WAT browning and thus contributes to the development of obesity.

Methods: Adipocyte-specific Fas knockout (Fas^Δadipo) and control littermate (Fas^F/F) mice were fed a regular chow diet or a high-fat diet (HFD) for 20 weeks. Energy expenditure was assessed by indirect calorimetry, and browning was determined in subcutaneous WAT. In vitro, UCP1 was analyzed in subcutaneous murine adipocytes treated with or without Fas ligand. Moreover, FAS expression in WAT was correlated to UCP1 and percentage of body fat in human individuals.

Results: HFD-fed Fas^Δadipo mice displayed reduced body weight gain and blunted adiposity compared to control littermates. Concomitantly, whole-body energy expenditure and WAT browning were elevated. In cultured adipocytes, Fas ligand treatment blunted isoproterenol-induced UCP1 protein levels. In support of these findings in rodents, FAS expression in WAT correlated negatively with UCP1 but positively with adiposity in human individuals.

Conclusions: Fas activation in adipocytes contributes to HFD-associated adiposity in rodents and may be a therapeutic target to reduce obesity and associated diseases.

Abstract

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