Galnt2 neurons in the ventromedial hypothalamus counterregulate hypoglycemia via a brain-liver neurocircuit.

The brain relies heavily on glucose for energy resources, and thus prompt counterregulatory responses to hypoglycemia in connection with glucose production are fundamental. We identified a biphasic pattern in blood and hypothalamic glucose dynamics during prolonged fasting, revealing an additional threshold-dependent mechanism for counterregulation. This mechanism is mediated by a ventromedial hypothalamus (VMH)→paraventricular hypothalamic nucleus (PVH)→lateral paragigantocellular nucleus (LPGi)→liver neurocircuit that detects neuroglycopenia and transmits neural signals to drive hepatic glucose production via intrahepatic sympathetic activation. Using viral tracing, single-nucleus RNA sequencing, and various unbiased methods, we identified Galnt2 as both a genetic marker and molecular brake of VMH glucose-inhibited neurons, modulating the glycemic threshold for hypoglycemia perception and metabolic homeostasis. Our results highlight a VMHGalnt2-originated brain-liver neurocircuit that perceives and counterregulates hypoglycemia and may pave the way to innovative therapeutic strategies against metabolic disorders characterized by glucose dysregulation.