Short‐Term Unacylated Ghrelin Administration Improves Pyruvate Tolerance Without Chronically Altering Skeletal Muscle, Liver, or Adipose Tissue Insulin Response in Healthy Rats

Unacylated ghrelin (unAG) is a metabolically active hormone, acutely stimulating fatty acid oxidation in skeletal muscle while promoting lipogenesis and inhibiting lipolysis in adipose tissue. Given these acute effects, we hypothesized that repeated unAG administration would improve skeletal muscle insulin response and that this would be associated with reduced muscle lipid storage. We treated healthy male Sprague-Dawley rats with twice-daily subcutaneous unAG (200 μg; 400 μg total daily) for 5 days. UnAG treatment did not alter glucose uptake or AKT activation basally, or in response to low or high insulin concentrations when assessed ex vivo in oxidative or glycolytic skeletal muscle, or when muscle was pre-exposed to a high-palmitate stress. Protein content of mitochondrial markers (CPT1B, citrate synthase, COXIV) also remained unchanged with treatment in both muscle types. Interestingly, UnAG-treated animals had a reduced glycemic response to pyruvate administration; however, content of hepatic glucose production-associated proteins and liver AKT response to insulin remained unchanged. UnAG treatment tended to increase LPL protein content in visceral adipose tissue (p = 0.07), but did not alter AKT or HSL phosphorylation in response to an insulin bolus in either subcutaneous or visceral adipose tissue. Finally, triacylglycerol content in the red and white gastrocnemius muscle, as well as in the liver, was unchanged by unAG administration. Overall, these findings indicate that short-term unAG treatment improves pyruvate tolerance, but that it does not exert persistent metabolic changes to skeletal muscle, liver, or adipose tissue substrate metabolism in healthy rats.