An investigation into the impact of deleting one copy of the glutaredoxin-2 gene on diet-induced weight gain and the bioenergetics of muscle mitochondria in female mice fed a high fat diet

Abstract

Our group recently documented that male mice containing a deletion for one copy of the glutaredoxin-2 (Grx2) gene were completely protected from developing diet-induced obesity (DIO). Objectives: Here, we conducted a similar investigation but with female littermates. Results: In comparison to our recent publication using male mice, exposure of WT and GRX2+/- female mice to a HFD from 3-to-10 weeks of age did not induce any changes in body mass, circulating blood glucose, food intake, hepatic glycogen levels, or abdominal fat pad mass. Examination of the bioenergetics of muscle mitochondria revealed no changes in the rate of superoxide ( )/hydrogen peroxide (H 2 O 2 ) or O 2 consumption under different states of respiration or alterations in lipid peroxidation adduct levels regardless of mouse strain or diet. Additionally, we measured the bioenergetics of mitochondria isolated from liver tissue and found that partial loss of GRX2 augmented respiration but did not alter ROS production. Discussion: Overall, our findings demonstrate there are sex differences in the protection of female GRX2+/- mice from DIO, fat accretion, intrahepatic lipid accumulation, and the bioenergetics of mitochondria from muscle and liver tissue.

Fatty acid oxidation drives hydrogen peroxide production by α-ketoglutarate dehydrogenase

“…Few studies have investigated the sex effects on these individual sources and their overall contributions towards total mH 2 O 2 generation. Using different substrate and inhibitor combinations and transgenic mouse models, we had previously shown in several studies PDH and KGDH display rates for mH 2 O 2 generation that can be up to ∼6-fold higher in male liver mitochondria when compared to the female littermates (Gill et al , 2020; Mallay et al , 2019; Wang et al ., 2023). This was also the case for dihydroorotate dehydrogenase (DHODH), an oxidoreductase embedded in the mitochondrial inner membrane that is required for pyrimidine biosynthesis (Koufos & Mailloux, 2023).…”

Mitochondrial hydrogen peroxide production by pyruvate dehydrogenase and α-ketoglutarate dehydrogenase in oxidative eustress and oxidative distress

“…Importantly, we had identified Glrx2 as a major mediator for these reactions in liver mitochondria, but only in males, not females ( 80 ). The sex dimorphic effect in PSSG adduct formation in liver mitochondria was related to differences in redox tone and mH 2 O 2 buffering capacity ( 80 , 108 ). Indeed, liver mitochondria from female rodents and humans have greater antioxidant capacity and redox tone, better mitochondrial coupling between nutrient oxidation and ATP production, and increased proton leaks, which reduces protonic backpressure to limit ROS production ( 11 , 108 , 109 ).…”

“…This was accompanied by the induction of steatosis and liver dysfunction ( 115 ). Notably, Grlx2 null female mice exhibit no increased sensitivity towards HFD-induced MAFLD, and its loss did not alter the efficiency of OxPhos or redox tone when compared to wild-type littermates fed the same diet ( 108 ). PDH and KGDH in Glrx2-null mice display increased glutathionylation and deactivation in livers ( 96 ).…”