title: Early leptin intervention reverses perturbed energy balance regulating hypothalamic neuropeptides in the pre- and postnatal calorie-restricted female rat offspring.
abstract: Pre- and postnatal calorie restriction is associated with postnatal growth restriction, reduced circulating leptin concentrations, and perturbed energy balance. Hypothalamic regulation of energy balance demonstrates enhanced orexigenic (NPY, AgRP) and diminished anorexigenic (POMC, CART) neuropeptide expression (PN21), setting the stage for subsequent development of obesity in female Sprague-Dawley rats. Leptin replenishment during the early postnatal period (PN2-PN8) led to reversal of the hypothalamic orexigenic:anorexigenic neuropeptide ratio at PN21 by reducing only the orexigenic (NPY, AgRP), without affecting the anorexigenic (POMC, CART) neuropeptide expression. This hypothalamic effect was mediated via enhanced leptin receptor (ObRb) signaling that involved increased pSTAT3/STAT3 but reduced PTP1B. This was further confirmed by an increase in body weight at PN21 in response to intracerebroventricular administration of antisense ObRb oligonucleotides (PN2-PN8). The change in the hypothalamic neuropeptide balance in response to leptin administration was associated with increased oxygen consumption, carbon dioxide production, and physical activity, which resulted in increased milk intake (PN14) with no change in body weight. This is in contrast to the reduction in milk intake with no effect on energy expenditure and physical activity observed in controls. We conclude that pre- and postnatal calorie restriction perturbs hypothalamic neuropeptide regulation of energy balance, setting the stage for hyperphagia and reduced energy expenditure, hallmarks of obesity. Leptin in turn reverses this phenotype by increasing hypothalamic ObRb signaling (sensitivity) and affecting only the orexigenic arm of the neuropeptide balance.
authors: Department of Pediatrics, Division of Neonatology and Developmental Biology and Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California.
authors: Leena Caroline
authors: LC
authors: Gibson
authors: Bo-Chul
authors: BC
authors: Shin
authors: Yun
authors: Y
authors: Dai
authors: William
authors: W
authors: Freije
authors: Sudatip
authors: S
authors: Kositamongkol
authors: John
authors: J
authors: Cho
authors: Sherin U
authors: SU
authors: Devaskar
mesh_terms: D000367:Age Factors; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D031204:Caloric Restriction; D002149:Energy Intake / Q000187:drug effects*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000473:pathology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D054369:Agouti-Related Protein; D020738:Leptin; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D011333:Pro-Opiomelanocortin
keywords: AgRP; CART; NPY; POMC; STAT3; energy expenditure; fetal programming; hypothalamus; leptin
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