While the ventromedial hypothalamic nucleus (VMN), especially the dorsomedial VMN (dmVMN), plays important roles in the control of blood glucose and energy balance, the subpopulations of VMN neurons that comprise the dmVMN have remained poorly defined. To identify dmVMN subpopulations in an unbiased manner, we performed single nucleus RNA-seq on mouse VMN and clustered the VMN neurons into subtypes based upon their transcriptional profiles (T-types). This analysis revealed over a dozen distinct T-types that can be organized hierarchically into 5 major classes of neurons that exhibit distinct anatomic distributions within the VMN (dm, ventrolateral, and tuberal). Several dmVMN T-types expressed marker genes known to contribute to the control of energy balance and glucose homeostasis (e.g., Lepr, Tcf7l2), and many of these genes were expressed in distinct T-types, suggesting the existence of multiple T-types that modulate metabolism, each of which may play distinct roles in metabolic control. Indeed, exposure to high-fat diet induced obesity (DIO) provoked transcriptional changes only in a subset of VMN T-types. Furthermore, while some DIO-induced transcriptional changes were common to all affected T-types, many changes were unique to a single T-type. Together, these findings not only identify the distinct subpopulations of dmVMN neurons in an unbiased manner, but they also reveal specific dmVMN subpopulations that respond to the metabolic perturbations associated with obesity, as well as the unique transcriptional responses of each subpopulation to these perturbations.
A. Rupp: Research Support; Self; Novo Nordisk A/S. A. Affinati: Research Support; Self; Novo Nordisk Inc. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc.