Developmental reprogramming of the melanocortin neurons regulates energy homeostasis

The central melanocortin neurons regulate satiety in mammalian species. Proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) play crucial and opposing roles in regulating food intake. POMC neurons promote satiety by releasing the anorexigenic peptide a-melanocyte-stimulating hormone (a-MSH), while AgRP neurons promote hunger through the release of the orexigenic peptides AgRP and neuropeptide Y (NPY). While distinct in function, these neurons arise, in part, from shared neuronal precursors during development. In mice, Pomc mRNA first appears in the developing hypothalamus at embryonic (E) day E10.5. The number of Pomc-expressing neurons gradually increases, reaching a peak around E13.5. However, Pomc expression in these neurons does not dictate terminal cell fate; instead, more than half of them lose Pomc expression as they adopt other peptidergic identities by the early postnatal period. Remarkably, some Pomc precursors begin expressing Npy, a marker for AgRP neurons, giving rise to a subset of adult AgRP neurons. However, the molecular mechanisms governing the fate switch between two antagonistic feeding neurons, and its physiological implications, have remained unknown. Overall design: We conducted a single-cell multiomic analysis of Pomc-lineage neurons (hereafter referred to as PL neurons) in the adult mediobasal hypothalamus. To label PL neurons, we generated double transgenic mice (Pomc-Cre; R26LSL-Sun1-sfGFP), in which PL neurons were permanently marked by the expression of a nuclear GFP (Sun1-sfGFP). Under a stereomicroscope, we isolated the mediobasal hypothalamus from adult mice, extracted, and purified GFP+ nuclei via fluorescence-activated cell sorting (FACS).