Elucidating the roles of adipocyte KAT8 in lipoatrophy and systemic insulin resistance

Project Summary: Adipocytes are highly specialized cells that have a number of functions including lipid storage, insulin sensitivity, and significant endocrine capabilities. Obesity is the primary disease of fat cells and the most common metabolic disorder in the industrial world. Obesity affects > 30% of the adult population in the United States and is a major risk factor for the development of Type 2 diabetes, cardiovascular disease, and hypertension. Diminished or excess adiposity and/or altered adipocyte function can have a substantial negative impact on metabolic health. Substantial advances in understanding adipocyte biology have revealed that adipose tissue is a vital contributor to systemic metabolic health. Therefore, the identification and study of proteins that contribute to adipocyte function can enhance our understanding of a variety of metabolic disease states. KAT8 is a lysine acetyltransferase (KAT) that has been shown to play a role in DNA damage repair, autophagy, apoptosis, and tumorigenesis. Although KAT8 is an important component of many cellular processes and has been linked to several types of cancers, it is clear that it has cell- and tissue-specific roles, and the function of KAT8 in adipocytes is poorly defined. Our unpublished data indicate that adipocyte KAT8 is important for systemic metabolic health. A large genome-wide association study identified KAT8 as part of a novel locus that significantly contributed to body mass index and other metabolic phenotypes. In vivo studies reveal that adipose tissue KAT8 protein levels are altered by obesity in mice. These data coupled with our results from new KAT8 mouse models indicate that there is a strong rationale for investigating the function(s) of KAT8 in adipocytes. The long-term objective of our proposed studies is to understand how adipocyte KAT8 contributes to adipose tissue function and systemic metabolic homeostasis. These studies are significant because they will provide novel insights into the roles of KAT8 in regulating fat cell function, adipose tissue production of reactive oxygen species, and the adipose tissue microenvironment within subcutaneous and visceral white adipose depots as well as brown adipose tissue.