Deletion of the Glutaredoxin-2 Gene Protects Mice from Diet-Induced Weight Gain, Which Correlates with Increased Mitochondrial Respiration and Proton Leaks in Skeletal Muscle.

The aim of this study was to determine whether deleting the gene encoding glutaredoxin-2 (GRX2) could protect mice from diet-induced weight gain. Subjecting wild-type littermates to a high fat diet (HFD) induced a significant increase in overall body mass, white adipose tissue hypertrophy, lipid droplet accumulation in hepatocytes, and higher circulating insulin and triglyceride levels. In contrast, GRX2 heterozygotes (GRX2) fed an HFD had a body mass, white adipose tissue weight, and hepatic and circulating lipid and insulin levels similar to littermates fed a control diet. Examination of the bioenergetics of muscle mitochondria revealed that this protective effect was associated with an increase in respiration and proton leaks. Muscle mitochondria from GRX2 mice had a ∼2- to 3-fold increase in state 3 (phosphorylating) respiration when pyruvate/malate or succinate served as substrates and a ∼4-fold increase when palmitoyl-carnitine was being oxidized. Proton leaks were ∼2- to 3-fold higher in GRX2 muscle mitochondria. Treatment of mitochondria with either guanosine diphosphate, genipin, or octanoyl-carnitine revealed that the higher rate of O consumption under state 4 conditions was associated with increased leaks through uncoupling protein-3 and adenine nucleotide translocase. GRX2 mitochondria also had better protection from oxidative distress. For the first time, we demonstrate that deleting the gene can protect from diet-induced weight gain and the development of obesity-related disorders. Deleting the gene protects mice from diet-induced weight gain. This effect was related to an increase in muscle fuel combustion, mitochondrial respiration, proton leaks, and reactive oxygen species handling. 31, 1272-1288.