Mice with Fabp4-Cre ablation of Arid5b are resistant to diet-induced obesity and hepatic steatosis. (15th May 2021)

• Record Type: Journal Article
• Authors: Whitson, Robert H.; Li, Shu-Lian; Zhang, Guoxiang; Larson, Garrett P.; Itakura, Keiichi
• Is Part Of: Molecular and cellular endocrinology. Volume 528(2021)
• Publication Date: 2021-05-15
• Subjects: Arid5b -- Obesity -- Diet -- Steatosis; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2021.111246
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Mice with global deletion of Arid5b expression are lean and resistant to diet-induced obesity, and Arid5b is required for adipogenesis in a variety of in vitro models. To determine whether the lean phenotype of Arid5b −/− mice can be explained by its absence in adipose tissues, we generated mice with Fabp4 -mediated ablation of Arid5b . Arid5b expression was ablated in adipocytes, from Fabp4-CRE pos ; Arid5b FLOX/FLOX (FSKO) mice. FSKO mice were not lean when maintained on standard chow, but males were resistant to weight gains when placed on high-fat diets (HFD). This was mainly due to decreased lipid accumulation in subcutaneous (inguinal) white adipose tissue (IWAT), and the liver. Lipid accumulation proceeded normally in gonadal WAT (GWAT) and glucose intolerance developed to the same degree in FSKO and WT controls when subjected to HFD. CD68-positive macrophages were also significantly reduced in both inguinal and gonadal fat depots. RNA-Seq analysis of IWAT adipocytes from FSKO mice on HFD revealed significant decreases in the expression of genes associated with inflammation. Although Arid5b expression was normal in livers of FSKO mice, tissue weight gains and triglyceride accumulation, and expression of genes involved in lipid metabolism were markedly reduced in livers of FSKO mice on HFD. These results suggest that Arid5b plays a critical role in lipid accumulation in specific WAT depots, and in the inflammatory signaling from WAT depots to liver that lead to lipid accumulation and hepatic steatosis. Highlights: Mice with Fabp4-CRE mediated ablation of Arid5b expression (FSKO) are resistant to diet-induced obesity. FSKO mice show reduced lipid accumulation in IWAT when subjected to a high fat diet (HFD). FSKO mice are resistant to HFD-driven hepatic steatosis. Arid5b ablation profoundly changes the expression of inflammatory response and lipid accumulation genes in liver and IWAT. WAT from FSKO mice has significantly less CD68 + macrophage invasion when subjected to HFD.