Roles of FoxO1 and Sirt1 in the central regulation of food intake.

The hypothalamus is the center of controlling food intake and energy expenditure by integrating information on energy status, i.e. adiposity and nutrient signals. Especially, two types of neurons in the arcuate nucleus of the hypothalamus, anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons, play vital roles in regulating feeding and energy expenditure. On the other hand, insulin and leptin are hormones that control food intake via regulating POMC and AgRP expression. FoxO1 is a downstream effecter of insulin signaling and Sirt1 is an NAD(+)-dependent deacetylase, both of which have been reported to play important roles in the regulation of metabolism in various organs including liver, pancreas, muscle, adipose tissue and hypothalamus. Histological analyses revealed that FoxO1 and Sirt1 are expressed in both AgRP and POMC neurons where FoxO1 localizes to the nucleus in the fasted, while to the cytoplasm in the refed condition. In contrast, hypothalamic Sirt1 protein is decreased in the fasted condition due to increased ubiquitination of Sirt1. In rodents, overexpression of FoxO1 in the hypothalamus by adenovirus microinjection induces hyperphagia and body weight gain, and simultaneous overexpression of Sirt1 suppresses these phenotypes. FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of AgRP and POMC through transcriptional squelching, and Sirt1 suppresses AgRP expression. In conclusion, we propose that FoxO1 and Sirt1 in hypothalamus are key regulators of energy homeostasis and are molecular targets for the development of new strategy of treating obesity.