Abstract
Exercise under fasting conditions induces a switch to lipid metabolism, eliciting beneficial metabolic effects. Knowledge of signaling responses underlying metabolic adjustments in such conditions may help to identify therapeutic strategies. Therefore, we studied the effect of mild exercise on rats submitted to food withdrawal at thermoneutrality (28°C) for 3 days. Animals were housed at thermoneutrality rather than the standard housing temperature (22°C) to avoid beta‐adrenergic signaling responses that themselves affect metabolism and well‐being. Quantitative analysis of multi‐organ mRNA levels, myofibers, and serum metabolites shows that this protocol (a) boosts fat oxidation in muscle and liver, (b) reduces lipogenesis and increases gluconeogenesis in liver, (c) increases serum acylcarnitines (especially C4OH) and ketone bodies and the use of the latter as fuel in muscle, (d) increases Type I myofibers, and (e) is associated with an increased thyroid hormone uptake and metabolism in muscle. In addition, stool microbiome DNA analysis revealed that food withdrawal dramatically alters the presence of bacterial genera associated with ketone metabolism. Taken together, this protocol induces a drastic switch toward increased lipid and ketone metabolism compared to exercise or food withdrawal alone, which may prove beneficial and may involve local thyroid hormones, which may be regarded as exercise mimetics.
Highlights
Fasting/food withdrawal elicits rapid metabolic adaptations in skeletal muscle as well as in other organs, and this is observed both in rodents and humans (De Lange et al, 2007)
We show here that food withdrawal at thermoneutrality modulates the response of mild exercise toward a strong oxidative stimulus
The transcriptional response toward a switch versus fatty acid oxidation by mild exercise and by food withdrawal at thermoneutrality was enhanced when both stimuli were combined (e.g., PGC-1α in muscle and liver, and pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) in muscle), which indicates that long-term responses are programed, with a lasting effect that prevails after the initial stimuli cease
Summary
Fasting/food withdrawal elicits rapid metabolic adaptations in skeletal muscle as well as in other organs, and this is observed both in rodents and humans (De Lange et al, 2007). The potential beneficial effects of exercise, alone or in combination with fasting/food withdrawal on metabolic parameters, have extensively been studied both in animal models and in humans (Jaspers et al, 2017). Up to now, studies on metabolic effects of fasting/food withdrawal and exercise in rodents, either including single exercise bouts (Zheng et al, 2015) or long-term protocols based on caloric restriction/intermittent fasting and exercise (Marosi et al, 2018), are performed at temperatures inducing cold-stress (20°C–22°C). We assessed the effect of the above protocol on (a) serum levels of thyroid hormone, the action of which is known to partially mimic the response to exercise (Aldiss et al, 2019) and (b) compositional changes in the stool microbiome, reflecting the gut's impact on metabolism
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