Exercise is required to maintain unacylated ghrelin response in adult male rat skeletal muscle, regardless of dietary fat consumption.

Unacylated ghrelin (unAG) stimulates fatty acid oxidation (FAO) in isolated male rat skeletal muscle. However, 6 weeks of high-fat feeding results in "ghrelin resistance," or loss of this effect. Recent work has indicated that sedentary behavior may be a main contributor to the loss of skeletal muscle unAG response, potentially representing an early disruption in lipid metabolism in the development of metabolic disease. Therefore, the objective of this study was to investigate whether exercise is required to maintain the stimulatory effect of unAG on FAO in skeletal muscle and if the exercise intensity needed is dependent on dietary fat intake. Male rats were fed either a low- or high-fat diet for 6 weeks while remaining sedentary, or performing low- or high-intensity exercise. Soleus muscle strips were isolated and assessed for their ability to respond to unAG by increasing FAO. High-intensity exercise preserved unAG response under both low-fat and high-fat dietary conditions, an effect not observed in sedentary or low-exercise groups. Additional soleus muscle strips were collected from all groups to assess the activation of the AMP-activated protein kinase-acetyl-CoA carboxylase axis and Ca2+ signaling in response to unAG; however, these pathways were not found to be significantly activated. Exercise also increased corticotropin-releasing factor 2 receptor content, the putative receptor through which unAG signals in skeletal muscle, whereas high-fat feeding had an overall effect to reduce it. However, unAG treatment did not activate cAMP/protein kinase A signaling. These findings demonstrate a protective role of exercise in maintaining skeletal muscle unAG response, although mechanisms remain to be fully elucidated. SIGNIFICANCE STATEMENT: Unacylated ghrelin stimulates fatty acid oxidation and protects insulin response in skeletal muscle; this response is lost with physical inactivity. We demonstrate that high-intensity exercise preserves this response, potentially due to changes in corticotropin-releasing factor 2 receptor content.