Regulation of MPCs and KAT8 During Adipogenesis and Nutritional Regulation

Abstract

Obesity is a global epidemic characterized by an expansion of adipose tissue. Adipose tissue, composed of adipocytes and a stromal vascular fraction, is an endocrine organ that regulates whole body homeostasis. Obesity leads to the dysregulation of adipocytes and is often associated with increased susceptibility to metabolic diseases such as Type II diabetes mellitus (T2DM). Understanding the mechanisms by which adipocyte function and development are regulated is crucial. Mitochondrial pyruvate carriers (MPCs) are transmembrane proteins that transport pyruvate from the cytosol into the mitochondrial matrix to generate acetyl CoA. Although MPCs have been studied extensively, their roles in adipocytes are not known. To study the role of MPCs in adipocytes, we assessed the requirement of MPC1 for adipogenesis, the expression of MPCs in adipose tissue, and the nutritional regulation of MPCs during diet-induced obesity (DIO). Our novel studies show that MPCs are not required for adipogenesis but are highly expressed in brown adipose tissue (BAT), and that MPC expression levels are regulated by DIO in the BAT of male mice. KAT8 is a lysine acetyltransferase that plays a role in DNA damage repair, apoptosis, and tumorigenesis. Although KAT8 is an important component of many cellular processes, its role in adipocytes is unknown. Notably, a large genome-wide association study identified KAT8 as part of a novel locus that significantly contributed to variations in body mass index and other metabolic phenotypes. Hence, we examined the expression and regulation of KAT8 in adipocytes. In vitro experiments revealed that KAT8 expression was required for adipogenesis but did not affect turnover rates of peroxisome proliferator-activated receptor γ (PPARγ) and fatty acid synthase (FASN). Our novel in vivo data demonstrates that KAT8 is highly expressed at the protein level in white adipose tissue (WAT) depots, upregulated by DIO in the iWAT and gWAT of male mice, and upregulated by refeeding after fasting in adipose tissue (AT) depots. We have observed that KAT8 expression is required for adipogenesis in vitro and is nutritionally regulated in WAT in vivo. Collectively, these studies have identified an epigenetic modifier that plays a previously unidentified role in adipocyte development and function.