Loss of Uncoupling Protein 3 Attenuates Western Diet–Induced Obesity, Systemic Inflammation, and Insulin Resistance in Rats

Objective Uncoupling protein 3 (UCP3) is a mitochondrial carrier related to fatty acid metabolism. Although gene variants of UCP3 are associated with human obesity, their contribution to increased adiposity remains unclear. This study investigated the impact that loss of UCP3 has on diet‐induced obesity in rats. Methods Male UCP3 knockout rats (ucp3 −/− ) and wild‐type littermates (ucp3 +/+ ) were fed a high‐fat, high‐carbohydrate Western diet for 21 weeks. Body composition was analyzed by EchoMRI. Whole‐body insulin sensitivity and rates of tissue glucose uptake were determined by using hyperinsulinemic‐euglycemic clamp. Changes in tissue physiology were interrogated by microscopy and RNA sequencing. Results Loss of UCP3 decreased fat mass gain, white adipocytes size, and systemic inflammation. The ucp3 −/− rats also exhibited preserved insulin sensitivity and increased glucose uptake in interscapular brown adipose tissue (iBAT). Brown adipocytes from ucp3 −/− rats were protected from cellular degeneration caused by lipid accumulation and from reactive oxygen species–induced protein sulfonation. Increased glutathione levels in iBAT from ucp3 −/− rats were linked to upregulation of genes encoding enzymes from the transsulfuration pathway in that tissue. Conclusions Loss of UCP3 partially protects rats from diet‐induced obesity. This phenotype is related to induction of a compensatory antioxidant mechanism and prevention of iBAT whitening.