Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

NASIF S*; DE SOUZA FS*; GONZÁLEZ LE; YAMASHITA M; ORQUERA DP; LOW MJ; RUBINSTEIN M

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2015 vol. 112

0027-8424

Food intake and body weight regulation depend on proper expressionof the proopiomelanocortin gene (Pomc) in a group of neuronslocated in the mediobasal hypothalamus of all vertebrates. Theseneurons release POMC-encoded melanocortins, which are potent anorexigenicneuropeptides, and their absence from mice or humansleads to hyperphagia and severe obesity. Although the pathophysiologyof hypothalamic POMC neurons is well understood, the geneticprogram that establishes the neuronal melanocortinergic phenotypeand maintains a fully functional neuronal POMC phenotype throughoutadulthood remains unknown. Here, we report that the earlyexpression of the LIM-homeodomain transcription factor Islet 1 (ISL1)in the developing hypothalamus promotes the terminal differentiationof melanocortinergic neurons and is essential for hypothalamic Pomcexpression since its initial onset and throughout the entire lifetime.Wedetected ISL1 in the prospective hypothalamus just before the onset ofPomc expression and, from then on, Pomc and Isl1 coexpress. ISL1binds in vitro and in vivo to critical homeodomain binding DNA motifspresent in the neuronal Pomc enhancers nPE1 and nPE2, and mutationsof these sites completely disrupt the ability of these enhancers todrive reporter gene expression to hypothalamic POMC neurons intransgenicmice and zebrafish. ISL1 is necessary for hypothalamic Pomcexpression during mouse and zebrafish embryogenesis. Furthermore,conditional Isl1 inactivation from POMC neurons impairs Pomc expression,leading to hyperphagia and obesity. Our results demonstrate thatISL1 specifies the identity of hypothalamic melanocortin neurons andis required for melanocortin-induced satiety and normal adipositythroughout the entire lifespan.