Hypothalamic Sirt1 regulates food intake in a rodent model system.
Sirt1 is an evolutionarily conserved NAD(+) dependent deacetylase involved in a wide range of processes including cellular differentiation, apoptosis, as well as metabolism, and aging. In this study, we investigated the role of hypothalamic Sirt1 in energy balance. Pharmacological inhibition or siRNA mediated knock down of hypothalamic Sirt1 showed to decrease food intake and body weight gain. Central administration of a specific melanocortin antagonist, SHU9119, reversed the anorectic effect of hypothalamic Sirt1 inhibition, suggesting that Sirt1 regulates food intake through the central melanocortin signaling. We also showed that fasting increases hypothalamic Sirt1 expression and decreases FoxO1 (Forkhead transcription factor) acetylation suggesting that Sirt1 regulates the central melanocortin system in a FoxO1 dependent manner. In addition, hypothalamic Sirt1 showed to regulate S6K signaling such that inhibition of the fasting induced Sirt1 activity results in up-regulation of the S6K pathway. Thus, this is the first study providing a novel role for the hypothalamic Sirt1 in the regulation of food intake and body weight. Given the role of Sirt1 in several peripheral tissues and hypothalamus, potential therapies centered on Sirt1 regulation might provide promising therapies in the treatment of metabolic diseases including obesity.
Cakir
Işin
I
Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, United States of America.
Perello
Mario
M
Lansari
Omar
O
Messier
Norma J
NJ
Vaslet
Charles A
CA
Nillni
Eduardo A
EA
D000107:Acetylation; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007031:Hypothalamus / Q000201:enzymology / Q000378:metabolism*; D053486:Melanocortins / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044101:Receptors, Melanocortin / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
D051858:Forkhead Transcription Factors; D053486:Melanocortins; D009419:Nerve Tissue Proteins; D011333:Pro-Opiomelanocortin; D044101:Receptors, Melanocortin; D019893:Ribosomal Protein S6 Kinases; D056564:Sirtuin 1; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1