Single-cell profiling identifies obesity-disrupted brain glucose sensing

Neuronal nutrient sensing in the hypothalamus and brainstem is thought to regulate energy and glucose homeostasis, yet how these brain regions respond to elevated adiposity or blood glucose remains unclear. We performed single-nucleus RNA-sequencing on 75,787 cells from the arcuate nucleus, ventromedial hypothalamus, and dorsal vagal complex of control diet- and high-fat diet (HFD)-fed male mice following intravenous glucose or saline infusion. HFD broadly altered gene expression across cell types, including Th/Slc6a3, Agrp, Ghrh, and Trh/Cxcl12 neurons. In control diet-fed mice, hyperglycemia triggered transcriptional responses conserved across brain regions in astrocytes and oligodendrocytes, and a response in Ghrh neurons, consistent with reduced neuronal activity. The transcriptional responses to hyperglycemia were largely absent or reversed after HFD. Genes enriched in both mouse and human GHRH neurons were located in loci genetically linked to human glycemic traits. These findings point to the brain's intrinsic capacity to sense hyperglycemia and suggest that this detection system is profoundly impaired in obesity.