Fat storage‐inducing transmembrane protein 2 (FIT2) is less abundant in type 2 diabetes, and regulates triglyceride accumulation and insulin sensitivity in adipocytes

Abstract

Fat storage-inducing transmembrane protein 2 (FIT2) aids in partitioning of cellular triacylglycerol into lipid droplets. A genome-wide association study reported FITM2-R3H domain containing like-HNF4A locus to be associated with type 2 diabetes (T2DM) in East Asian populations. Mice with adipose tissue (AT)-specific FIT2 knockout exhibited lipodystrophic features, with reduced AT mass, insulin resistance, and greater inflammation in AT when fed a high-fat diet. The role of FIT2 in regulating human adipocyte function is not known. Here, we found FIT2 protein abundance is lower in subcutaneous and omental AT obtained from patients with T2DM compared with nondiabetic control subjects. Partial loss of FIT2 protein in primary human adipocytes attenuated their lipid storage capacity and induced insulin resistance. After palmitate treatment, triacylglycerol accumulation, insulin-induced Akt (Ser-473) phosphorylation, and insulin-stimulated glucose uptake were significantly reduced in FIT2 knockdown adipocytes compared with control cells. Gene expression of proinflammatory cytokines IL-18 and IL-6 and phosphorylation of the endoplasmic reticulum stress marker inositol-requiring enzyme 1α were greater in FIT2 knockdown adipocytes than in control cells. Our results show for the first time that FIT2 is associated with T2DM in humans and plays an integral role in maintaining metabolically healthy AT function.-Agrawal, M., Yeo, C. R., Shabbir, A., Chhay, V., Silver, D. L., Magkos, F., Vidal-Puig, A., Toh, S.-A. Fat storage-inducing transmembrane protein 2 (FIT2) is less abundant in type 2 diabetes, and regulates triglyceride accumulation and insulin sensitivity in adipocytes.

Significant transcriptomic changes are associated with the inhibitory effects of 5-aza-2-deoxycytidine during adipogenic differentiation of MG-63 cells

“…One of the main gene Diacylglycerol O-acyltransferases (DGAT2) is involved in triacylglycerol metabolism ( Bhatt-Wessel et al, 2018 ). While FITM2 (Fat Storage Inducing Transmembrane Protein 2) is a storage protein and its abundance is affected in type 2 diabetes ( Agrawal et al, 2019 ). The two isoforms PCK1 and 2 of phosphoenolpyruvate carboxy kinase are involved in the gluconeogenesis; these enzymes are dysregulated in the obesity and diabetes ( Beale et al, 2007 ).…”

Dynamic Regulation of Lipid Droplet Biogenesis in Plant Cells and Proteins Involved in the Process

“…Mammals have two FIT proteins, FIT1 and FIT2. FIT2 has been confirmed to play an important role in LD formation [ 14 , 50 ]. Biochemical analyses confirmed that FIT2 directly and specifically binds to both TAG and its immediate precursor DAG, while purified FIT2 proteins have no intrinsic TAG biosynthetic activity.…”

Role of Seipin in Human Diseases and Experimental Animal Models

“…Moreover, similar to seipin, other ER-located proteins involved in LD biogenesis such as fat storage-inducing FIT2, Atlastin, REEP1 and so on are also closely associated with human diseases. For example, FIT2 has been certified to play a key role in lipodystrophy [ 172 ], diabetes mellitus [ 173 , 174 ], and hepatocellular carcinoma [ 175 ], as well as doxorubicin-mediated cardiotoxicity [ 176 ], and the underlying mechanisms are also incompletely clear. Therefore, it is of great significance to study the precious mechanism of these proteins in diseases, and studies focusing on seipin are excellent examples of them.…”