Publication in detail

Diabetologia 2018 May;61(5):1167-1179. doi: 10.1007/s00125-018-4571-9. Epub 2018 Feb 24.

Increased Ifi202b/IFI16 expression stimulates adipogenesis in mice and humans.

Stadion, M; Schwerbel, K; Graja, A; Baumeier, C; Rödiger, M; Jonas, W; Wolfrum, C; Staiger, H; Fritsche, A; Häring, HU; Klöting, N; Blüher, M; Fischer-Posovszky, P; Schulz, TJ; Joost, HG; Vogel, H; Schürmann, A

Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany. German Center for Diabetes Research (DZD), Munich, Neuherberg, Germany. Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany. Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland. Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany. Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany. IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany. Department of Medicine, University of Leipzig, Leipzig, Germany. Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

Abstract:
AIMS/HYPOTHESIS: Obesity results from a constant and complex interplay between environmental stimuli and predisposing genes. Recently, we identified the IFN-activated gene Ifi202b as the most likely gene responsible for the obesity quantitative trait locus Nob3 (New Zealand Obese [NZO] obesity 3). The aim of this study was to evaluate the effects of Ifi202b on body weight and adipose tissue biology, and to clarify the functional role of its human orthologue IFI16. METHODS: The impact of Ifi202b and its human orthologue IFI16 on adipogenesis was investigated by modulating their respective expression in murine 3T3-L1 and human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocytes. Furthermore, transgenic mice overexpressing IFI202b were generated and characterised with respect to metabolic traits. In humans, expression levels of IFI16 in adipose tissue were correlated with several variables of adipocyte function. RESULTS: In mice, IFI202b overexpression caused obesity (Δ body weight at the age of 30 weeks: 10.2 ± 1.9 g vs wild-type mice) marked by hypertrophic fat mass expansion, increased expression of Zfp423 (encoding the transcription factor zinc finger protein [ZFP] 423) and white-selective genes (Tcf21, Tle3), and decreased expression of thermogenic genes (e.g. Cidea, Ucp1). Compared with their wild-type littermates, Ifi202b transgenic mice displayed lower body temperature, hepatosteatosis and systemic insulin resistance. Suppression of IFI202b/IFI16 in pre-adipocytes impaired adipocyte differentiation and triacylglycerol storage. Humans with high levels of IFI16 exhibited larger adipocytes, an enhanced inflammatory state and impaired insulin-stimulated glucose uptake in white adipose tissue. CONCLUSIONS/INTERPRETATION: Our findings reveal novel functions of Ifi202b and IFI16, demonstrating their role as obesity genes. These genes promote white adipogenesis and fat storage, thereby facilitating the development of obesity-associated insulin resistance.

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