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.