VMHdm/cSF-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/cSF-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/cSF-1 neurons regulate skeletal muscle function remain unclear. Here, we show that VMHdm/cSF-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/cSF-1 neurons combined with genetically-engineered mice and surgical manipulation of the sympathoadrenal activity. RESULTS: Optogenetic activation of VMHdm/cSF-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 ß2 adrenergic receptor (ß2AdR) is essential for VMHdm/cSF-1 neurons-mediated increases in skeletal muscle PGC1-α. Specifically, both adrenalectomy and ß2AdR knockout block augmented skeletal muscle PGC1-α by VMHdm/cSF-1 neuronal activation. Optogenetic functional mapping reveals that downstream nodes of VMHdm/cSF-1 neurons are functionally redundant to increase circulating epinephrine and skeletal muscle PGC1-α. CONCLUSIONS: Collectively, we propose that VMHdm/cSF-1 neurons-skeletal muscle pathway, VMHdm/cSF-1 neurons→multiple downstream nodes→the adrenal gland→skeletal muscle ß2AdR, underlies augmented skeletal muscle function for metabolic adaptations.

Glucose-Lowering by Leptin in the Absence of Insulin Does Not Fully Rely on the Central Melanocortin System in Male Mice.

Central leptin administration can ameliorate hyperglycemia in insulin-deficient rodent models independently of insulin; however, the underlying neuronal mechanism are unclear. Here, we investigate the contribution of key elements within the central melanocortin system by examining whether central leptin injection can ameliorate hyperglycemia in total insulin-deficient mice that either lacked melanocortin 4 receptors (MC4Rs) in the whole body [knockout (KO); MC4R KO] or selectively, in single-minded homolog 1 (SIM1)-expressing neurons (SIM1ΔMC4R). We further investigated the contribution of leptin receptors (LEPRs) in agouti-related protein (AgRP)-expressing neurons (AgRP∆LEPR). Leptin injections into the cerebral ventricle attenuated mortality and elevated blood glucose in total insulin-deficient MC4R KO mice. Total insulin-deficient SIM1ΔMC4R mice exhibited the same magnitude reduction of blood glucose in response to leptin injections as MC4R KO mice, suggesting SIM1 neurons are key to MC4R-mediated, insulin-independent, glucose-lowering effects of leptin. Central leptin injection also partially rescued glucose levels in total insulin-deficient AgRP∆LEPR mice. In brain slice studies, basal discharge of AgRP neurons from mice with total insulin deficiency was increased and leptin partially reduced their firing rate without membrane potential hyperpolarization. Collectively, our findings indicate that, contrary to glucose-lowering effects of leptin in the presence of insulin or partial insulin deficiency, MC4Rs in SIM1 neurons and LEPRs in AgRP neurons are not solely responsible for glucose-lowering effects of leptin in total insulin deficiency. This indicates that the central melanocortin system operates with other neuronal systems to fully mediate glucose-lowering effects of leptin in an insulin-independent manner.