Central Sirt1 Regulates Body Weight and Energy Expenditure Along With the POMC-Derived Peptide alpha-MSH and the Processing Enzyme CPE Production in Diet-Induced Obese Male Rats

作者：Cyr Nicole E; Steger Jennifer S; Toorie Anika M; Yang Jonathan Z; Stuart Ronald; Nillni Eduardo A^*

来源：Endocrinology, 2015, 156(3): 961-974.

DOI：10.1210/en.2014-1970

In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of hypothalamic Sirt1 in body weight and energy balance regulation is debated. The first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague-Dawley rats. Central inhibition of Sirt1 decreased body weight and food intake as a result of a forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin POMC) and decrease in the orexigenic Agouti-related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which in turn increased phosphorylated FoxO1 via improved insulin/phosphorylated AKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the alpha-melanocyte-stimulating hormone (alpha-MSH) maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product alpha-MSH released into the paraventricular nucleus. Increased in alpha-MSH led to augmented TRH levels and circulating T3 levels (triiodothyronine, thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic-pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics.

• 出版日期2015-3