title: Programmed hyperphagia in offspring of obese dams: Altered expression of hypothalamic nutrient sensors, neurogenic factors and epigenetic modulators.
abstract: Maternal overnutrition results in programmed offspring obesity, mediated in part, by hyperphagia. This is remarkably similar to the effects of maternal undernutrition on offspring hyperphagia and obesity. In view of the marked differences in the energy environment of the over and under-nutrition exposures, we studied the expression of select epigenetic modifiers associated with energy imbalance including neurogenic factors and appetite/satiety neuropeptides which are indicative of neurogenic differentiation. HF offspring were exposed to maternal overnutrition (high fat diet; HF) during pregnancy and lactation. We determined the protein expression of energy sensors (mTOR, pAMPK), epigenetic factors (DNA methylase, DNMT1; histone deacetylase, SIRT1/HDAC1), neurogenic factors (Hes1, Mash1, Ngn3) and appetite/satiety neuropeptides (AgRP/POMC) in newborn hypothalamus and adult arcuate nucleus (ARC). Despite maternal obesity, male offspring born to obese dams had similar body weight at birth as Controls. However, when nursed by the same dams, male offspring of obese dams exhibited marked adiposity. At 1 day of age, HF newborn males had significantly decreased energy sensors, DNMT1 including Hes1 and Mash1, which may impact neuroprogenitor cell proliferation and differentiation. This is consistent with increased AgRP in HF newborns. At 6 months of age, HF adult males had significantly increased energy sensors and decreased histone deactylases. In addition, the persistent decreased Hes1, Mash1 as well as Ngn3 are consistent with increased AgRP and decreased POMC. Thus, altered energy sensors and epigenetic responses which modulate gene expression and adult neuronal differentiation may contribute to hyperphagia and obesity in HF male offspring.
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. 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, David Geffen School of Medicine at UCLA and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Han
authors.affiliation: Perinatal Research Laboratories, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ross
mesh_terms: D050154:Adiposity; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001066:Appetite / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001835:Body Weight; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D002149:Energy Intake; D044127:Epigenesis, Genetic; D005260:Female; D006963:Hyperphagia / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D044342:Malnutrition / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D039382:Maternal Nutritional Physiological Phenomena; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D011247:Pregnancy; D051381:Rats; D012527:Satiation / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; D051792:Basic Helix-Loop-Helix Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D009419:Nerve Tissue Proteins; D058570:TOR Serine-Threonine Kinases; D000072056:Transcription Factor HES-1; C515197:AGRP protein, rat; C499318:Ascl1 protein, rat; C489735:Hes1 protein, rat; C498696:Neurog3 protein, rat; C000619382:Dnmt1 protein, rat; C546845:mTOR protein, rat
keywords: Energy sensors; Epigenetic factors; bHLH genes