<i>Adrβ2</i> in skeletal muscle cells is required for exercise-induced Pgc1α but not for metabolic benefits of exercise on diet-induced obesity

β2-Adrenergic receptor ( Adrβ2 ) is the most abundant form of adrenergic receptors in skeletal muscle. Our previous studies have shown that the ventromedial hypothalamic nucleus (VMH) regulates metabolic benefits of exercise, potentially by skeletal muscle Adrβ2 . Although a large body of literature has shown the importance of Adrβ2 on skeletal muscle physiology, it remains unexplored whether skeletal muscle Adrβ2 contributes to metabolic benefits of exercise, such as prevention of diet-induced obesity (DIO). Here, we generated mice lacking Adrβ2 in skeletal muscle cells (SKM Adrβ2 ) and tested whether SKM Adrβ2 is required for metabolic benefits of exercise on DIO. Deletion of SKM Adrβ2 completely abolished the induction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α) in skeletal muscle by β2-agonist, which is a potent activator of Pgc-1α. Exercise upregulates Pgc-1α, which regulates a broad range of skeletal muscle physiology, including hypertrophy and mitochondrial function. Deletion of SKM Adrβ2 hampers augmented Pgc-1α in skeletal muscle by a single bout of exercise. Intriguingly, we found that deletion of SKM Adrβ2 increased endurance capacity. Further, our data showed that body weight in DIO mice lacking SKMAdrβ2 is comparable to that of control DIO mice during exercise training, suggesting that deletion of SKM Adrβ2 did not affect the metabolic benefits of exercise in DIO. Collectively, our data indicate that SKM Adrβ2 contributes to exercise-induced transcriptional changes and endurance capacity, however, it is not required for exercise benefits on bodyweight in DIO mice.