Autophagy activation, not PGC-1α, may mediate exercise-induced improvements in glucose handling during diet-induced obesity

Abstract

Prevalence of glucose intolerance is at alarming levels. Efforts to promote mitochondrial biogenesis through PGC-1α to mitigate glucose intolerance have been controversial. However, physical activity remains a primary means to alleviate the condition.

Purpose

To determine combined effects of muscle-specific overexpression of PGC-1α and physical activity on glucose handling during diet-induced obesity.

Methods

Wild-type (WT, ∼20) and PGC-1α muscle transgenic (MCK-PGC-1α, ∼20) mice were given Western diet (WD) at 8 wks age and allowed to consume food ab libitum throughout the study. At 12 wks age, all animals were divided into sedentary (SED) or voluntary wheel running (VWR) interventions. At 7, 11, and 15 wks age animals underwent glucose tolerance (GTT) and graded exercise tests (GXT). At 16 wks age tissues were collected.

Results

At 11 wks MCK-PGC-1α animals had 50% greater glucose tolerance integrated area under the curve (IAUC) compared to WT. However, at 15 wks, SED animals had similarly greater GTT IAUC compared to VWR, regardless of genotype; furthermore, SED animals demonstrated reduced exercise capacity compared to prior time points which was not seen in VWR. Voluntary distance run/day correlated with GTTs in VWR-WT, but not VWR-MCK-PGC-1α mice. VWR and genotype independently resulted in greater LC3II/I ratio, suggesting enhanced autophagosome formation, which correlated with exercise-induced GTT improvements.

Conclusion

Artificially increasing mitochondrial content does not protect from lipid-induced pathologies nor does it augment exercise adaptations. Physical activity ameliorates the effects of lipid-overload-induced glucose intolerance, an effect that appears related to enhanced autophagy activation.

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