Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing

•Hypothalamic POMC neurons are heterogeneous and can broadly divided into 4 groups.•Cell surface receptors are major drivers for the segregation.•Unexpectedly, 28% of POMC-cells show signatures typical of AgRP/NPY neurons.•Only 12% express leptin receptor, indicating response to leptin is likely indirect.

ObjectiveArcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture.MethodsUsing single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons.ResultsOf 163 neurons, 118 expressed high levels of Pomc with little/no Agrp expression and were considered “canonical” POMC neurons (P+). The other 45/163 expressed low levels of Pomc and high levels of Agrp (A+P+). Unbiased clustering analysis of P+ neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P+ neurons expressed the leptin receptor (Lepr) compared with 58% (26/45) of A+P+ neurons. In contrast, the insulin receptor (Insr) was expressed at similar frequency on P+ and A+P+ neurons (64% and 55%, respectively).ConclusionThese data reveal arcuate POMC neurons to be a highly heterogeneous population.Accession Numbers: GSE92707.