Islet 1 Specifies the Identity of Hypothalamic Melanocortin Neurons and is Critical for Normal Food Intake and Adiposity in Adulthood

Food intake and body weight regulation depend on a group of hypothalamic neurons that release satiety-induced neuropeptides known as melanocortins. Central melanocortins are encoded by the proopiomelanocortin gene (Pomc), and mice and humans carrying deleterious mutations in the Pomc gene display hyperphagia and severe obesity. Although the importance of these neurons is well understood, the genetic program that establishes hypothalamic melanocortin neurons and maintains normal Pomc expression levels remains unknown. Here, we combined molecular neuroanatomical and biochemical analyses with functional genetic studies in transgenic mice and zebrafish and discovered that the transcription factor Islet 1 determines the identity of central melanocortin neurons during early brain development and is critical for melanocortin-induced satiety and normal adiposity throughout the entire lifetime.