1567-P: Hepatic ALKBH5 Regulation of Glucose and Lipid Metabolism

Obesity is a worsening global health crisis leading to increased risk of long-term complications such as type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH), dyslipidemia and cardiovascular disease. Identifying novel molecular mechanisms regulating the connection between obesity, hepatic insulin resistance and progression of NASH is critical to develop new therapeutic options for these patients. Previous work has shown that reversible N6-methyladenosine (m6A) RNA methylation patterns are altered in and regulate metabolic disease in the pancreatic beta cell and liver. However, these studies have primarily focused on the m6A writer proteins that direct placement of m6A methyl groups, while our study explores the role of m6A eraser protein AlkBH5 in regulating metabolic pathways in the liver. To test the hypothesis that hepatic ALKBH5 is required to maintain normal glucose homeostasis, insulin sensitivity and lipid metabolism under physiologic conditions and in response to metabolic stress we used liver-specific Alkbh5 knockout (A5KO) mice and evaluated changes in weight gain, body composition, glucose tolerance, insulin sensitivity, fasting insulin levels, and gluconeogenesis in response to a chow versus Western diet (WD). In physiologic conditions (chow), A5KO mice have decreased glucose tolerance with no other significant phenotypic changes compared to controls. Exposure to metabolic stress (WD) caused (1) greater weight gain with increased visceral fat in control compared to A5KO mice, (2) decreased glucose tolerance compared to chow in both genotypes, (3) decreased glucose mobilization in A5KO mice on WD compared to chow, with no significant differences in controls, and (4) no significant differences in global insulin sensitivity. These studies demonstrate that A5KO mice are protected against weight gain upon exposure to metabolic stress with decreased glucose tolerance and mobilization compared to controls, establishing a role for hepatic ALKBH5 in regulating glucose and lipid metabolism. Disclosure K.Aamodt: None. M.Polay: None. V.R.Salerno gonzales: None. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago. Funding National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007699-39, 5T32DK007260-45); Pediatric Endocrine Society