DMC (2′,4′‐dihydroxy‐6′‐methoxy‐3′,5′‐dimethylchalcone) enhances exercise tolerance via the AMPK‐SIRT1‐PGC‐1α pathway in mice fed a high‐fat diet

Abstract Obesity is caused by an imbalance between energy intake and energy expenditure. This study aimed to determine the effects and mechanisms of 2′,4′‐dihydroxy‐6′‐methoxy‐3′,5′‐dimethylchalcone (DMC) on exercise tolerance in high‐fat diet (HFD)‐fed mice. Male C57BL/6J mice were randomly divided into two categories (7 groups [ n = 8]): sedentary (control [CON], HFD, 200 mg/kg DMC, and 500 mg/kg DMC) and swimming (HFD, 200 mg/kg DMC, and 500 mg/kg DMC). Except the CON group, all other groups were fed HFD with or without DMC intervention for 33 days. The swimming groups were subjected to exhaustive swimming (three sessions/week). Changes in swimming time, glucolipid metabolism, body composition, biochemical indicators, histopathology, inflammation, metabolic mediators, and protein expression were assessed. DMC combined with regular exercise improved endurance performance, body composition, glucose and insulin tolerance, lipid profile, and the inflammatory state in a dose‐dependent manner. Further, DMC alone or combined with exercise could restore normal tissue morphology, reduce fatigue‐associated markers, and boost whole‐body metabolism and the protein expression of phospho‐AMP‐activated protein kinase alpha/total‐AMP‐activated protein kinase alpha (AMPK), sirtuin‐1 (SIRT1), peroxisome‐proliferator‐activated receptor gamma coactivator 1alpha (PGC‐1α), and peroxisome proliferator‐activated receptor alpha in the muscle and adipose tissues of HFD‐fed mice. DMC exhibits antifatigue effects by regulating glucolipid catabolism, inflammation, and energy homeostasis. Furthermore, DMC exerts a synergistic exercise‐related metabolic effect via the AMPK‐SIRT1‐PGC‐1α signaling pathway, suggesting that DMC is a potential natural sports supplement with mimicked or augmented exercise effects for obesity prevention.