6‐Gingerol Improves Ectopic Lipid Accumulation, Mitochondrial Dysfunction, and Insulin Resistance in Skeletal Muscle of Ageing Rats: Dual Stimulation of the AMPK/PGC‐1α Signaling Pathway via Plasma Adiponectin and Muscular AdipoR1

Scope This study investigates the dual actions of 6‐gingerol in stimulating both plasma adiponectin and muscular adiponectin receptor signaling in naturally ageing rats. Methods and results Twenty‐two‐month‐old male SD rats were treated with 6‐gingerol (0.2 mg kg–1, once daily) for 7 weeks. 6‐Gingerol can attenuate age‐associated high plasma triglyceride, glucose, and insulin concentrations under fasting conditions as well as suppress the increase in the HOMA‐IR index and inhibit the decrease of muscular p‐Akt/Akt protein in ageing rats, which indicates an improvement of systemic and muscular insulin sensitivity. Accompanying these changes, treatment with 6‐gingerol attenuates excessive triglyceride accumulation, enhances mitochondrial function, and promotes a transition from a fast‐ to slow‐fiber type and muscle oxidative metabolism in the red gastrocnemius of ageing rats. More importantly, 6‐gingerol not only increases the plasma and adipose tissue adiponectin concentrations, but also elevates muscular AdipoR1 expression and activates downstream AMPK phosphorylation as well as upregulates PGC‐1α in vivo and in vitro. Conclusion 6‐Gingerol may improve ectopic lipid accumulation, mitochondrial dysfunction, and insulin resistance in skeletal muscle of ageing rats. These effects rely, at least in part, on the elevated plasma adiponectin concentration and muscle AdipoR1 level to dually activate the AMPK/PGC‐1α signaling pathway. A mechanistic model is proposed in which 6‐gingerol improves ectopic lipid accumulation, mitochondrial dysfunction, and insulin resistance in skeletal muscle of ageing rats through elevating plasma adiponectin and muscular AdipoR1 to dually activate the AMPK/PGC‐1α signaling pathway.