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Uncoupling Protein 3 Deficiency Prevents Whitening of Brown Fat and Preserves Insulin Sensitivity in High‐Fat Fed Rats
Author(s) -
Lomax Tyler M.,
Ashraf Sadia,
Wiseman Jessica M.,
Edwards Kristin S.,
Harmancey Romain
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.752.4
Subject(s) - ucp3 , endocrinology , medicine , uncoupling protein , insulin resistance , type 2 diabetes , insulin , biology , fatty acid , obesity , chemistry , diabetes mellitus , brown adipose tissue , biochemistry
Uncoupling protein 3 (UCP3), a mitochondrial anion carrier promoting fatty acid oxidation in myocytes, is down‐regulated in animal models with obesity, insulin resistance and type 2 diabetes. Although mutations in UCP3 have been linked to obesity in humans, their contribution to increased adiposity and insulin resistance is still unclear. The goal of this study was to investigate the effect of UCP3 loss on the development of high‐fat diet‐induced obesity. UCP3‐deficient rats were generated using CRISPR‐Cas9 genome editing, and male littermates were maintained on a high‐fat diet (HFD) for 14 weeks starting at 8 weeks of age. Compared with wild type control animals, UCP3‐deficient rats experienced a reduction in total body weight gain and body fat percentage. Perirenal fat depots were also lighter and overall contained smaller adipocytes. High‐fat feeding markedly induced whitening of subscapular brown fat depots in wild type rats, which was characterized at the subcellular level by an accumulation of large lipid droplets. Interestingly, whitening of brown fat was reduced in UCP3‐deficient rats. Preservation of brown fat structure in the UCP3 knockout rats was associated with a dramatic change in mitochondrial cristae organization. Although plasma triacylglycerol, free fatty acids, and total cholesterol levels were not different from that of wild type rats, UCP3 deficiency led to a reduction in circulating levels of tumor necrosis factor‐α, improved systemic insulin sensitivity, and improved glucose tolerance. In conclusion, loss of UCP3 unexpectedly reduces fat mass gain and preserves insulin sensitivity under high‐fat feeding in rats. We propose that the improvement of insulin sensitivity is due to decreased fat accumulation in adipose tissue and subsequent reduction of chronic inflammation driven by increased mitochondrial function in brown adipose tissue. Support or Funding Information This work was supported by NIH Grants R01HL136438, R00HL112952, P01HL051971, and P20GM104357 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .