Abstract 697: Protein Sumoylation in the Adipocyte Modulates Inflammatory Responses, Diabetes and Cardiovascular Disease
Adipocyte dysfunction is highly correlated with the development of diabetes. Protein SUMOylation has emerged as important regulatory mechanisms for protein function. In this study, we show that mice with a genetic deletion of the SUMO-specific protease SENP1 gene in adipocytes (SENP1-apKO) develop a type 1 diabetes mellitus (T1DM), including hyperglycemia, glucose intolerance, and increased circulating diabetic markers insulin autoantibody, C-reactive protein and beta-hydroxybutyrate with normal lipid profiles. The pancreases of SENP1-apKO mice exhibit increased infiltration of T cells and inflammation-induced β-cell apoptosis. Detailed analyses indicate that proinflammatory cytokines produced by pancreatic adipocytes in SENP1-apKO mice precedes the onset of T1DM phenotype. Mechanistic studies show that NEMO, the NF-κB essential molecule, is a major target of SENP1 in the adipose tissues. SENP1 deletion in pancreatic adipocytes enhances NEMO SUMOylation at lysine 277/309, augmenting NF-κB activity, cytokine production and pancreatic inflammation. More importantly, NF-κB inhibitor could inhibit pre-diabetic cytokine production, beta cell damages and T1DM phenotype in SENP1-apKO mice. Our study has uncovered a novel mechanism for the onset and progression of T1DM associated with adipocyte dysfunction. The SENP-apKO mice also develop other cardiovascular disease phenotype and we will discuss potential mechanisms.
Author Disclosures: W. Min: None. L. Shao: None. J. Zhou: None. Q. Huang: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.