198-LB: The Loss of the Lysine Acetyltransferase KAT8 in Adipocytes Confers Lipodystrophy and Metabolic Dysfunction in Male and Female Mice

Abstract

KAT8, also known as MOF or MYST1, is a lysine acetyltransferase with both histone and non-histone substrates. While KAT8 is the major H4K16 acetyltransferase in Drosophila and mammals and is essential for embryonic development, its role in specific cell types is not well understood. Moreover, studies within the past decade have demonstrated lineage-, differentiation state-, or stress-dependent roles of KAT8. Our recent efforts have shown that KAT8 is necessary for in vitro adipogenesis prior to or during the proliferative phase. Notably, several, independent genetic studies reveal that single nucleotide polymorphisms (SNPs) within or near the KAT8 gene are associated with body mass index and/or waist circumference. To investigate the role of KAT8 in differentiated adipocytes and to understand the contribution of KAT8-deficient adipocytes to whole-body glucose and lipid metabolism, we generated both congenital and doxycycline-inducible adipocyte-specific knockout mice, in which Kat8 gene deletion occurs only in adiponectin-expressing cells. Adult mice lacking adipocyte KAT8 exhibited significant fat mass loss with no change in lean mass. While the size of inguinal and brown adipose tissue was significantly reduced in both sexes fed either chow or high-fat, high-sucrose (HFHS) diet, male mice also had decreased gonadal, retroperitoneal, and mesenteric depots. Histological assessments revealed substantial remodeling within adipose tissue depots, and these mice demonstrated reduced insulin sensitivity and increased lipid accumulation in the liver when fed HFHS diet. Although further investigation is necessary to identify KAT8 targets that confer lipodystrophy, these studies are the first to show the impact of the loss of adipocyte KAT8 in vivo. Disclosure A. J. Richard: n/a. T. M. Mendoza: None. J. M. Stephens: None. Funding National Institutes of Health COBRE P&F grant (P30 GM118430)