Single-Cell Analysis Reveals Cellular Heterogeneity and Regulatory Networks of Hypothalamic Leptin-Receptor Cells

Several hypothalamic cells regulating energy balance express leptin receptor (LepR), the primary target of the satiety hormone leptin. Single-cell RNA sequencing (scRNA-seq) has facilitated the discovery of a variety of hypothalamic cell types, although characterization of rare populations remains incomplete. We performed scRNA-seq on isolated hypothalamic LepR cells and identified eight neuronal clusters with diverse neurochemical profiles, including thyrotropin releasing hormone expressing populations, as well as 17 non-neuronal populations. Food restriction had a major impact on agouti-related protein (Agrp) neurons and on the expression of several genes with likely etiologic roles in obesity. Determination of transcription factor activity in LepR cell types revealed Rfx3 and Npdc1 as potential regulators of Agrp neurons response to fasting. Multiple clusters, including pro-opiomelanocortin (Pomc) neurons, were enriched for genome-wide association study signals for body mass index, a commonly used proxy phenotype for obesity. Our work provides details on the multi-functional nature of leptin's action in the hypothalamus.