Pre‐ and postnatal calorie restriction perturbs early hypothalamic neuropeptide and energy balance

Abstract

Energy balance is regulated by circulating leptin concentrations and hypothalamic leptin receptor (ObRb) signaling via STAT3 but inhibited by SOCS3 & PTP1B. Leptin signaling enhances anorexigenic neuropeptides and receptor (POMC, MC3-R, MC4-R) activation while suppressing orexigenic neuropeptides (NPY, AgRP). We investigated in a sex-specific manner the early (PN2) and late (PN21) postnatal hypothalamic mechanisms in response to intrauterine (IUGR), postnatal (PNGR) and combined (IPGR) calorie and growth restriction. At PN2, while both male and female IUGR were hypoleptinemic, hypothalamic leptin signaling in females was activated as seen by enhanced STAT3. In addition, increased SOCS3 and PTP1B supported early initiation of leptin resistance in females that led to elevated AgRP but diminished MC3-R and MC4-R. In contrast, males demonstrated leptin sensitivity seen as a reduction in PTP1B and MC3-R and MC4-R with no effect on neuropeptide expression. At PN21 with adequate postnatal caloric intake, a sex-specific dichotomy in leptin concentrations was seen in IUGR with euleptinemia in males indicative of persisting leptin sensitivity and hyperleptinemia in females consistent with leptin resistance, both with normal hypothalamic ObRb signaling, neuropeptides and energy balance. In contrast, superimposition of PNGR upon IUGR (IPGR) led to diminished leptin concentrations with enhanced PTP1B and an imbalance in arcuate nuclear NPY/AgRP and POMC expression that favored exponential hyperphagia and diminished energy expenditure post-weaning. We conclude that IUGR results in sex-specific leptin resistance mainly observed in females while PNGR and IPGR abolish this sex-specificity setting the stage for acquiring obesity after weaning.

Early life nutrient restriction impairs blood–brain metabolic profile and neurobehavior predisposing to Alzheimer’s disease with aging

“…However at PN50 while the PNGR/IPGR males continued to demonstrate protection by elevated CSF ketones, this protection was absent in age-matched females. While we did not measure insulin or IGF-I at these early stages in this study, we have previously assessed them and noted insulin and IGF-I to be lower in PNGR and IPGR groups versus CON (Abbasi et al, 2011; Shin et al, 2012; Thamotharan et al, 2005). These hormonal changes are congenial for the use of alternate substrates to fuel brain energy metabolism.…”

“…The study design generating four experimental groups consisting of CON, IUGR, PNGR and IPGR is shown schematically in Figure 1 (Garg et al, 2012b; Shin et al, 2012). …”

“…At birth, the litter size was culled to six to ensure no inter-litter postnatal nutritional variability. Cross-fostering of pups generated four experimental groups as previously described by us (Garg et al, 2006; Shin et al, 2012). Pups born to ad lib feeding control mothers were reared by either mothers on nutrient restriction from PN1 to PN21 (PNGR) or by control mothers (CON).…”

“…Rats were anesthetized at PN21 and PN50 with intraperitoneal injection of sodium pentobarbital (50 mg/kg) (Shin et al, 2012). CSF was collected from the cisterna magna compartment as previously described (Pegg et al, 2010).…”

“…Powdered brain was homogenized and sonicated either in cell lysis buffer (Cell Signaling Technology) or in PBS containing protease inhibitors (20 µg/ml pepstatin A, 20 µg/ml leupeptin, 30 µg/ml aprotinin, and 2 mM PMSF), 1% Nonidet P-40, and 5 mM EDTA as previously described (Shin et al, 2012). The resulting suspension was centrifuged at 10,000g at 4°C for 10 min, and the supernatant was subjected to Western blot analysis as previously described (Oak et al, 2006).…”