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0 reviewsSUMMARYThe brain relies heavily on glucose for energy resources, and thus prompt counterregulatory responses tohypoglycemia in connection with glucose production are fundamental. We identified a biphasic pattern inblood and hypothalamic glucose dynamics during prolonged fasting, revealing an additional thresholddependent 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 unbiasedmethods, we identified Galnt2 as both a genetic marker and molecular brake of VMH glucose-inhibitedneurons, modulating the glycemic threshold for hypoglycemia perception and metabolic homeostasis. Ourresults highlight a VMHGalnt2-originated brain-liver neurocircuit that perceives and counterregulates hypoglycemia and may pave the way to innovative therapeutic strategies against metabolic disorders characterizedby glucose dysregulation.