Elsevier

Molecular Metabolism

Volume 4, Issue 1, January 2015, Pages 15-24
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2014.10.003Get rights and content
Under a Creative Commons license
open access

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Ghrelin
Hypothalamus
Nutrition
Programming
Hormone
Tanycytes

Abbreviations

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

Cited by (0)

3

Eglantine Balland, Jyoti Parkash, Emilie Caron and Fanny Langlet contributed equally to this work.