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Mol Metab. 2014 Oct 24;4(1):15-24. doi: 10.1016/j.molmet.2014.10.003. eCollection 2015 Jan.

Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin.

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Inserm U1172, Jean-Pierre Aubert Research Center, University Lille 2, Lille 59045, France.
The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA ; Inserm U1172, Jean-Pierre Aubert Research Center, University Lille 2, Lille 59045, France.



Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the stomach that acts centrally to promote feeding behavior by binding to growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. Here, we examined whether neonatal overnutrition causes changes in the ghrelin system.


We used a well-described mouse model of divergent litter sizes to study the effects of postnatal overfeeding on the central and peripheral ghrelin systems during postnatal development.


Mice raised in small litters became overweight during lactation and remained overweight with increased adiposity as adults. Neonatally overnourished mice showed attenuated levels of total and acyl ghrelin in serum and decreased levels of Ghrelin mRNA expression in the stomach during the third week of postnatal life. Normalization of hypoghrelinemia in overnourished pups was relatively ineffective at ameliorating metabolic outcomes, suggesting that small litter pups may present ghrelin resistance. Consistent with this idea, neonatally overnourished pups displayed an impaired central response to peripheral ghrelin. The mechanisms underlying this ghrelin resistance appear to include diminished ghrelin transport into the hypothalamus.


Early postnatal overnutrition results in central resistance to peripheral ghrelin during important periods of hypothalamic development. Because ghrelin signaling has recently been implicated in the neonatal programming of metabolism, these alterations in the ghrelin system may contribute to the metabolic defects observed in postnatally overnourished mice.


ARH, arcuate nucleus; AgRP, agouti-related peptide; DMH, dorsomedial nucleus; GHSR, growth hormone secretagogue receptor; GOAT, ghrelin O-acyltransferase; Ghrelin; HFHS, high-fat/high-sucrose diet; Hormone; Hypothalamus; LHA, lateral hypothalamic area; MBH, mediobasal hypothalamus; ME, median eminence; NL, normal litters; NPY, neuropeptide Y; Nutrition; P, postnatal day; POMC, pro-opiomelanocortin; PVH, paraventricular nucleus; Programming; SL, small litter; Tanycytes

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