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.

Evidence of extraganglionic vagal mechanoreceptors in the mouse vagus nerve.

Vagal afferent neuronal somas are in the nodose and jugular ganglia. In this study, we identified extraganglionic neurons in whole-mount preparations of the vagus nerves from Phox2b-Cre-ZsGreen transgenic mice. These neurons are typically arranged in small clusters and monolayers along the cervical vagus nerve. Although infrequent, these neurons were sometimes observed along the thoracic and esophageal vagus. We performed RNAscope in situ hybridization and confirmed that the extraganglionic neurons detected in this transgenic mouse strain expressed vagal afferent markers (i.e., Phox2b and Slc17a6) as well as markers that identify them as potential gastrointestinal mechanoreceptors (i.e., Tmc3 and Glp1r). We also identified extraganglionic neurons in the vagus nerves of wild-type mice that were injected intraperitoneally with Fluoro-Gold, thereby ruling out possible anatomical discrepancies specific for transgenic mice. In wild-type mice, extraganglionic cells were positive for peripherin, confirming their neuronal nature. Taken together, our findings revealed a previously undiscovered population of extraganglionic neurons associated with the vagus nerve. Going forward, it is important to consider the possible existence of extraganglionic mechanoreceptors that transmit signals from the abdominal viscera in future studies related to vagal structure and function.

CB1Rs in VMH neurons regulate glucose homeostasis but not body weight.

Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.