title: Programmed hyperphagia secondary to increased hypothalamic SIRT1.
abstract: Small for gestational age (SGA) offspring exhibit reduced hypothalamic neural satiety pathways leading to programmed hyperphagia and adult obesity. Appetite regulatory site, the hypothalamic arcuate nucleus (ARC) contains appetite (NPY/AgRP) and satiety (POMC) neurons. Using in vitro culture of hypothalamic neuroprogenitor cells (NPC) which form the ARC, we demonstrated that SGA offspring exhibit reduced NPC proliferation and neuronal differentiation. bHLH protein Hes1 promotes NPC self-renewal and inhibits differentiation by repressing neuronal differentiation genes (Mash1, neurogenin3). We hypothesized that Hes1/Mash1 and ultimately ARC neuronal differentiation and expression of NPY/POMC neurons are influenced by SIRT1 which is a nutrient sensor and a histone deacetylase. Control dams received ad libitum food, whereas study dams were 50% food-restricted from pregnancy day 10 to 21 (SGA). In vivo studies showed that SGA newborns and adult offspring had increased protein expression of hypothalamic/ARC SIRT1 and AgRP with decreased POMC. Additionally, SGA newborns had decreased expression of hypothalamic neurogenic factors with reduced in vivo NPC proliferation. In vitro culture of hypothalamic NPCs showed similar changes with elevated SIRT1 binding to Hes1 in SGA newborn. Silencing SIRT1 increased NPC proliferation and Hes1 and Tuj1expression in both Control and SGA NPCs. Although SGA NPC proliferation remained below that of Controls, it was higher than Control NPCs in the absence of SIRT1 siRNA. The direct impact of SIRT1 on NPC proliferation and differentiation were further confirmed with pharmacologic SIRT1 inhibitor and activator. Thus, in SGA newborns elevated SIRT1 induces premature differentiation of NPCs, reducing the NPC pool and cell proliferation.
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502. Electronic address: mdesai@obgyn.humc.edu.
authors.forename: Mina
authors.initials: M
authors.lastname: Desai
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Tie
authors.initials: T
authors.lastname: Li
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Guang
authors.initials: G
authors.lastname: Han
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ross
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D006963:Hyperphagia / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D054369:Agouti-Related Protein; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin; D056564:Sirtuin 1; D000072056:Transcription Factor HES-1; C515197:AGRP protein, rat; C499318:Ascl1 protein, rat; C489735:Hes1 protein, rat; C488368:Sirt1 protein, rat
keywords: Appetite and satiety neuropeptides; Hypothalamic neuroprogenitor cells; Proliferation and differentiation; Sirtinol and resveratrol; bHLH genes