Restricted accessResearch articleFirst published online 2019-12
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.
Results:
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 O2 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.
Innovation:
For the first time, we demonstrate that deleting the Grx2 gene can protect from diet-induced weight gain and the development of obesity-related disorders.
Conclusions:
Deleting the Grx2 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. Antioxid. Redox Signal. 31, 1272–1288.
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