Hypothalamic neurosphere progenitor cells in low birth-weight rat newborns: Neurotrophic effects of leptin and insulin

A low birth-weight (LBW) offspring exhibits reduced hypothalamic neural satiety pathways and dysregulated signaling leading to programmed hyperphagia and adult obesity. Hypothalamic appetite circuits develop during early life, under the influence of neurotrophic hormones (leptin and insulin). Notably, LBW newborns have reduced plasma leptin and insulin levels. As neurons and glia arise from neuronal progenitor cells (NPC), we postulated that a programmed impairment of NPCs may contribute to reduced hypothalamic neural pathway development in a LBW offspring. Control dams received ad libitum food, whereas study dams were 50% food-restricted from pregnancy day 10 to 21 (LBW). At day 1 of age, hypothalamic NPCs were cultured as neurospheres (NS) and treated with leptin/insulin. We analyzed in vitro NPC proliferation and differentiation into neurons/astrocytes, expression of signal molecules promoting proliferation (activated Notch1 and its downstream target, Hes1) and in vivo NPC proliferation and migration. LBW offspring had impaired in vivo evidence of NPC division and migration, and reduced in vitro evidence of proliferation and differentiation to neurons and astrocytes, under basal and stimulated conditions. The reduced Notch1 and Hes1 expression in LBW neurosphere, under both basal and stimulated conditions, suggests a reduced progenitor cell population or reduced cell density within the neurosphere.

Research Highlights► Evidence of neuronal progenitor cells (NPC) in the peri-third ventricular region. ► Reduced in vivo proliferation and migration of NPC as evident by BrdU staining. ► Reduced basal proliferation and differentiation of hypothalamic NPCs cultures. ► Reduced leptin/insulin stimulated hypothalamic NPC proliferation/differentiation. ► Downregulated Notch1/Hes1 mediated mechanism for reduced NPC proliferation.