Analysis script for snRNA-seq of the mediobasal hypothalamus and dorsal vagal complex
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. In control diet-fed mice, hyperglycemia triggered conserved transcriptional responses in glial cells, and growth hormone-releasing hormone (Ghrh) neurons, consistent with reduced Ghrh neuron activity. HFD broadly altered gene expression across brain cell types, and activity-associated transcriptional responses in Ghrh and other neurons were largely absent or reversed. Genes enriched in both mouse and human GHRH neurons were located in loci genetically linked to human glycemic traits. These findings reveal the brain’s intrinsic capacity to sense hyperglycemia and demonstrate that this detection system is profoundly impaired in obesity.