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.

Programmed hyperphagia in offspring of obese dams: Altered expression of hypothalamic nutrient sensors, neurogenic factors and epigenetic modulators

“…Using hypothalamic NPC from newborn rat, we have previously confirmed direct impact of SIRT1 on NPC proliferation and differentiation by both SIRT1 siRNA and exposure to SIRT1 pharmacologic inhibitor and activator. 15 In the present study, despite evidence of maternal overnutrition during fetal life, one day old HF newborns demonstrated normal hypothalamic SIRT1 expression. Nutrition influences on SIRT1 expression remains conflicting, with studies demonstrating that fasting both decreases and increases hypothalamic SIRT1.…”

“…14 Low birth weight offspring have altered energy sensing, specifically SIRT1 within the hypothalamic arcuate nucleus (ARC), a putative site of appetite regulation. 15 Our studies utilizing both in vivo models and fetal/newborn neuroprogenitor cell (NPC) culture, have indicated that these altered energy sensors effect neurogenic factors which reduce NPC proliferation, induce premature NPC differentiation, and ultimately result in an increase of hypothalamic eating-stimulatory (NPY; neuropeptide Y and AgRP; agouti-related protein) versus eating-inhibitory (POMC; pro-opiomelanocortin) neurons and peptide expression. 15;16;41 …”

Metabolism disrupting chemicals and metabolic disorders

“…In rodent studies, female offspring exposed prenatally to DDT followed by a high fat diet for 12 weeks in adulthood developed glucose intolerance, hyperinsulinemia, dyslipidemia and altered bile acid metabolism as well as reduced energy expenditure and impaired thermogenesis [389]. DDT effects were also transmitted across generations resulting in obesity in the F3 generation [608]. …”

“…Imprinting, altered DNA methylation, histone modifications and copy number variants have all been implicated in transgenerational phenotype transmission as a result of exposure to chemicals or altered nutrition [610] [615-617]. Candidate sperm epimutations were also identified that could be involved in the etiology of the transgenerational obesity and other disease outcomes [618]. …”

Loss of Vagal Sensitivity to Cholecystokinin in Rats Born with Intrauterine Growth Retardation and Consequence on Food Intake

“…Animal studies have demonstrated that perinatal undernutrition may lead to a programmed hyperphagia that in the long term led to adult obesity (5). Previous studies in our laboratory demonstrated that low-protein (LP) rats eat more of a regular chow diet from weaning to 2-month old (6, 7).…”