TRAF3IP2 ablation protects against obesity‐associated glycemic dysregulation, elevated blood pressure, and endothelial dysfunction

Obesity and type 2 diabetes (T2D) are leading independent risk factors for cardiovascular disease morbidity and mortality. However, the precise molecular mechanisms underlying the development of cardiometabolic dysfunction in obesity and T2D remain largely elusive. The recently identified cytoplasmic adapter molecule TRAF3 Interacting Protein 2 (TRAF3IP2) is known to regulate various pathological stress pathways, including inflammation and oxidative stress, associated with obesity and T2D. Accordingly, we tested the hypothesis that TRAF3IP2 mediates metabolic and vascular dysfunction associated with chronic high fat/high sucrose (HFHS) feeding. The results show that HFHS feeding for 16 weeks (starting at 5 weeks of age) increased body weight and impaired glucose tolerance in wild‐type (WT) male and female mice relative to control chow‐fed mice ( P <0.05). Notably, glucose intolerance was attenuated in HFHS‐fed male and female homozygous TRAF3IP2 knockout (KO) mice ( P <0.05) compared to WT counterparts despite greater weight gain. Interestingly, male TRAF3IP2‐KO mice exhibited protection against HFHS feeding‐induced elevations in blood pressure (tail cuff plethysmography) and ex vivo aortic endothelial dysfunction ( P <0.05). However, female mice fed HFHS were protected against increases in blood pressure and impairments in aortic endothelial function and, thus, deletion of TRAF3IP2 was inconsequential ( P >0.05). In summary, our data show that TRAF3IP2 plays a causal role in obesity‐associated glucose intolerance, elevated blood pressure and endothelial dysfunction. These findings implicate TRAF3IP2 as a promising therapeutic target in cardiometabolic dysfunction associated with obesity. Support or Funding Information Dept. of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USADalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA Dept. of Biological Engineering, University of Missouri, Columbia, MO, USA Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, MO, USA Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA Laboratory of Immunoregulation, NIAID/NIH, Bethesda, MD, USA Dept. of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA Division of Cardiovascular Medicine, Department of Medicine, University of Missouri, Columbia, MO, USA