Aim
Ghrelin is a fasting induced hormone that signals energy deficit to the brain through the growth hormone secretagogue receptor (GHSR) to promote hunger, conserve energy, and stabilise blood glucose. Although GHSR is widely expressed in the brain, the neural circuits linking ghrelin signalling to glucose regulation remain unclear. The ventromedial hypothalamus (VMH) is a key centre for glucose sensing and metabolic control. We therefore investigated whether GHSR expressing neurons in the VMH, and ghrelin signalling within these neurons, regulate glucose homeostasis and metabolic adaptation to energy deficit.
Results
Single-cell and spatial transcriptomics identified VMH-GHSR neurons as a small, predominantly glutamatergic population enriched for metabolic-sensing genes. In vivo fibre photometry revealed that VMH-GHSR activity increases with ghrelin and decreases upon hypoglycaemia, or glucoprivation, indicating that these neurons encode interoceptive energy state. To establish gain-of-function effects, we manipulated VMH-GHSR activity using optogenetics and constitutive ion-channel activation (NaChBac). Acute optogenetic stimulation significantly accelerated glucose clearance during a glucose tolerance test. Similarly, constitutive activation via NaChBac demonstrated that sustained activity in VMH-GHSR neurons enhances glucose disposal and insulin sensitivity, supporting a role of these neurons in glucose regulation. Conversely, adult-onset VMH-specific GHSR deletion did not affect body weight under ad libitum conditions, but caused increased fasting glycaemia and whole-body insulin resistance. Hyperinsulinaemic–euglycaemic clamps revealed that this impairment was driven by defective suppression of hepatic glucose production and reduced peripheral glucose uptake. Under caloric restriction, VMH-GHSR deleted mice failed to conserve energy, displaying excessive lipid oxidation, elevated energy expenditure, and accelerated fat loss.
Conclusion
VMH GHSR neurons act as vital sensors that couple energy status to fuel utilization and blood glucose control. Deletion of GHSRs reveals a specific requirement for ghrelin signalling within these neurons, highlighting a brain circuit relevant to diabetes and metabolic disease.