NKX2.1 is critical for melanocortin neuron identity, hypothalamic Pomc expression and body weight

Food intake is tightly regulated by a group of neurons present in the mediobasal hypothalamus which activate satiety by releasing Pomc-encoded melanocortins. Although the relevance of hypothalamic POMC neurons in the regulation of energy balance and body weight is well appreciated, little is known about the transcription factors that establish their cellular fate, terminal differentiation and phenotypic maintenance. Here, we report that the transcription factor Nkx2.1 activates hypothalamic Pomc expression from early development to adulthood by binding to conserved canonical NKX motifs present in the neuronal Pomc enhancers nPE1 and nPE2. Transgenic and mutant mouse studies showed that the NKX motifs present in nPE1 and nPE2 are essential for their transcriptional enhancer activity. Early inactivation of Nkx2.1 in the ventral hypothalamus prevented the onset of Pomc expression and selective Nkx2.1 ablation from POMC neurons impaired Pomc expression and increased body weight and adiposity. These results demonstrate that NKX2.1 is critical in the early establishment of arcuate melanocortin neurons and the regulation of Pomc expression and body weight in adulthood.