title: Central Sirt1 regulates body weight and energy expenditure along with the POMC-derived peptide α-MSH and the processing enzyme CPE production in diet-induced obese male rats.
abstract: 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 α-melanocyte-stimulating hormone (α-MSH) maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product α-MSH released into the paraventricular nucleus. Increased in α-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.
authors.affiliation: Division of Endocrinology (N.E.C., J.S.S., A.M.T., J.Z.Y., R.S., E.A.N.), Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903; and Department of Molecular Biology, Cell Biology, and Biochemistry (E.A.N.), Brown University, Providence, Rhode Island 02912.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Cyr
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Steger
authors.forename: Anika M
authors.initials: AM
authors.lastname: Toorie
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Yang
authors.forename: Ronald
authors.initials: R
authors.lastname: Stuart
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Nillni
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology*; D043423:Carboxypeptidase H / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004734:Energy Metabolism / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D043423:Carboxypeptidase H; D004041:Dietary Fats; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D011333:Pro-Opiomelanocortin; D056564:Sirtuin 1; D000521:alpha-MSH; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C488368:Sirt1 protein, rat