VMHdm/c^SF-1 neuronal circuits regulate skeletal muscle PGC1-α via the sympathoadrenal drive

Objective: To adapt to metabolically challenging environments, the central nervous system (CNS) orchestrates metabolism of peripheral organs including skeletal muscle. The organ-communication between the CNS and skeletal muscle has been investigated, yet our understanding of the neuronal pathway from the CNS to skeletal muscle is still limited. Neurons in the dorsomedial and central parts of the ventromedial hypothalamic nucleus (VMHdm/c) expressing steroidogenic factor-1 (VMHdm/c^SF-1 neurons) are key for metabolic adaptations to exercise, including increased basal metabolic rate and skeletal muscle mass in mice. However, the mechanisms by which VMHdm/c^SF-1 neurons regulate skeletal muscle function remain unclear. Here, we show that VMHdm/c^SF-1 neurons increase the sympathoadrenal activity and regulate skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in mice via multiple downstream nodes. Methods: Optogenetics was used to specifically manipulate VMHdm/c^SF-1 neurons combined with genetically-engineered mice and surgical manipulation of the sympathoadrenal activity. Results: Optogenetic activation of VMHdm/c^SF-1 neurons dramatically elevates mRNA levels of skeletal muscle Pgc-1α, which regulates a spectrum of skeletal muscle function including protein synthesis and metabolism. Mechanistically, the sympathoadrenal drive coupled with β2 adrenergic receptor (β2AdR) is essential for VMHdm/c^SF-1 neurons-mediated increases in skeletal muscle PGC1-α. Specifically, both adrenalectomy and β2AdR knockout block augmented skeletal muscle PGC1-α by VMHdm/c^SF-1 neuronal activation. Optogenetic functional mapping reveals that downstream nodes of VMHdm/c^SF-1 neurons are functionally redundant to increase circulating epinephrine and skeletal muscle PGC1-α. Conclusions: Collectively, we propose that VMHdm/c^SF-1 neurons-skeletal muscle pathway, VMHdm/c^SF-1 neurons→multiple downstream nodes→the adrenal gland→skeletal muscle β2AdR, underlies augmented skeletal muscle function for metabolic adaptations.