1736-P: Insulin Resistance and Mitochondrial Dysfunction Mediated by Nat1 Deficiency

Abstract

Insulin resistance (IR) is fundamental to the pathophysiology of type 2 diabetes (T2D) and a major risk factor for cardiovascular disease (CVD). Therapeutic options for IR are limited, reinforcing the need to understand IR pathways with an aim to develop IR-specific medications. We previously identified human N-acetyl transferase 2 (NAT2) as a novel insulin sensitivity gene. In vitro and in vivo studies demonstrated an association of mouse Nat1 (ortholog of human NAT2) deficiency with both IR and mitochondrial dysfunction. However, the underlying mechanism of how Nat1 deficiency causes IR and mitochondrial dysfunction is unknown. Using engineered ascorbate peroxidase-proximity labeling in cells followed by mass spectrometry-based proteomic analysis, we are mapping Nat1 endogenous targets and Nat1 interacting proteins. Verification of the interacting proteins and functional validation will be achieved by co-immunoprecipitation, siRNA knockdown, glucose uptake and lipolysis assays, and mitochondrial functional assays in mouse liver cells and adipocytes. We have also created a liver specific Nat1-deficient mouse model and will determine whether this is sufficient to cause whole body changes in insulin sensitivity. Collectively, these studies will shed light on mechanism of how the novel IR gene Nat1 participates in the pathophysiology of IR, which is a necessary step for the development of new treatments for T2D and CVD. Disclosure P. Sangwung: None. M. Fathzadeh: None. J. Knowles: None. Funding American Diabetes Association (1-19-JDF-108 to J.K.); U.S. Public Health Service; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107437, R01DK106236, P30DK116074, 1R01DK116750 to J.K.)