Western Diet And Exercise Training Increase Mitochondrial Lipid Respiration In Male But Not Female Mice

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High-fat feeding in mice is a common model to investigate mitochondrial lipid metabolism during diet-induced obesity. Our previous work demonstrates 60% high-fat diet stimulates mitochondrial lipid respiration yet such fat content is higher than a typical western diet (~35% fat with higher sugar). Aerobic exercise training also stimulates mitochondrial lipid respiration, but the interaction with western diet is not clear. PURPOSE: We determined mitochondrial oxidative function in response to western diet in the absence and presence of concurrent exercise training. We hypothesized western diet would induce greater mitochondrial lipid respiration that would be further enhanced with exercise training. METHODS: Male and female C57BL/6J mice (n=5-7 per group for each sex) ate either western diet (WD) or low-fat diet (LFD) for 4 weeks, with a group of WD mice randomized to perform concurrent treadmill training (WD+Ex). At week 4, dual-energy x-ray absorptiometry was used to measure body composition and in-vivo substrate oxidation was assessed using metabolic cage indirect calorimetry. Ex-vivo mitochondrial oxidation was measured via high-resolution respirometry using isolated mitochondria from quadriceps muscles collected 36-hours after final exercise session (or rest). Respiration protocols included lipid (octanoyl-carnitine+malate) and non-lipid (glutamate+succinate) substrates. RESULTS: Among sedentary mice, WD had higher body weight and fat mass than LFD (P<0.0001), but only in males. WD had lower in-cage respiratory exchange ratio than LFD (P<0.05) regardless of sex, indicating greater whole-body reliance on lipids. In males, WD+Ex stimulated mitochondrial lipid respiration more so than WD alone (P<0.05). Females had no significant changes in mitochondrial lipid respiration. Non-lipid supported mitochondrial respiration was not significantly altered by WD or WD+Ex regardless of sex. CONCLUSION: In agreement with our hypothesis, WD stimulated lipid-specific mitochondrial respiration that further increased with Ex, but only in male mice. There were apparent sex differences such that females were protected against WD-induced weight gain alongside limited changes in mitochondrial lipid respiration.

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