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. 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

Gustav Collden  1 , Eglantine Balland  1 , Jyoti Parkash  1 , Emilie Caron  1 , Fanny Langlet  1 , Vincent Prevot  1 , Sebastien G Bouret  2
Affiliations

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

Gustav Collden et al. Mol Metab. .

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: 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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Figures

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Graphical abstract
Figure 1
Figure 1
Small litter rearing accelerates postnatal weight gain and causes long-term metabolic alterations. (A) Pre- and (B) post-weaning body weight curves in C57BL6 male mice raised in small (SL) and normal (NL) litters and fed a chow diet after weaning (n = 15–16 per group). (C) Cumulative food intake of adult NL and SL mice on chow diet (n = 8 per group). (D) Respiratory exchange ratio of adult NL and SL mice (n = 8 per group). (E) Body composition of adult SL and NL mice (n = 9–11 per group). (F) Weight gain, (H) change in total fat mass, and (I) fasting glycemia of adult SL and NL mice fed a high-fat/high-sucrose diet (HFHS) for 8 weeks (n = 10–15 per group). Values are shown as the mean ± SEM. *P < 0.05 versus NL.
Figure 2
Figure 2
Neonatal overfeeding attenuates ghrelin levels during postnatal life. Serum (A) total and (B) acyl ghrelin levels of P8, P12, P14, P16, P22, and P60 (adult) mice raised in normal litters (NL) and small (SL) litters (n = 4–10 per group). Relative expression of (C) Ghrelin and (D) Goat mRNA in the stomach of P14, P16, P22, and P60 (adult) mice raised in SL and NL (n = 4–6 per group). Values are shown as the mean ± SEM. *P < 0.05 versus NL.
Figure 3
Figure 3
Neonatal ghrelin injections have moderate effects on the metabolic phenotype of neonatally overfed mice. (A) Serum acyl ghrelin levels of P16 NL pups injected with saline and SL pups injected with ghrelin (5, 10, and 50 ug/kg i.p.) or saline (n = 2–3 per group). (B) Pre- and (C) post-weaning growth curves (body weights) of SL and NL mice neonatally injected with ghrelin (10 ug/kg i.p.) or saline (n = 7–26 per group); the black bar represents the injection period. (D) Lean mass, (E) fat mass, and (F) fasting glycemia of adult SL and NL mice neonatally injected with ghrelin (10 ug/kg i.p.) or saline (n = 7–11 per group). Values are shown as the mean ± SEM. *P < 0.05 versus NL saline; †P < 0.05 versus NL ghrelin; #P < 0.05 versus SL saline.
Figure 4
Figure 4
Attenuated central response to peripheral ghrelin in neonatally overfed pups. (A) Relative expression of Ghsr mRNA in the arcuate nucleus/median emimence of P14, P16, P22, and P60 (adult) mice raised in SLs and NLs (n = 4–5 per group). (B) Representative images and quantification of cFos-immunoreactive cells in the arcuate nucleus (ARH) 2 h after intraperitoneal (ip) administration of ghrelin (2 mg/kg) or saline alone in P14, P16, P22, and P60 mice raised in SLs and NLs (n = 4–7 per group). (C) Ghsr, (D) Npy, (E) Agrp, and (F) Pomc mRNA expression in the arcuate nucleus/median eminence of P14 SL and NL pups intraperitoneally injected with ghrelin (2 mg/kg i.p.) or saline alone (n = 3–5 per group). Values are shown as the mean ± SEM. (A) *P < 0.05 versus NL. (B) *P < 0.05 versus NL ghrelin; (C–E) *P < 0.05 versus saline (C–E). Scale bar, 200 um.
Figure 5
Figure 5
Peripheral ghrelin does not induce neuronal activation in the dorsomedial hypothalamic nucleus (DMH) during neonatal life. (A) Relative expression of Ghsr mRNA in the dorsomedial nucleus of P14, P16, P22, and P60 (adult) mice raised in SLs and NLs (n = 4–5 per group). (B) Representative images and quantification of cFos-immunoreactive cells in the dorsomedial nucleus (DMH) nucleus 2 h after intraperitopenal (ip) administration of ghrelin (2 mg/kg) or saline alone in P14, P16, P22, and P60 mice raised in SLs and NLs (n = 4–8 per group). Values are shown as the mean ± SEM. *P < 0.05 versus NL. Scale bar, 400 um.
Figure 6
Figure 6
Normal central response to central ghrelin in neonatally overfed pups. Representative images and quantification of cFos-immunoreactive cells in the arcuate nucleus (ARH) 90 min after intracerebroventricular (icv) administration of ghrelin (240 ug/ml) or saline alone in P14 mice raised in SLs and NLs (n = 3–6 per group). Values are shown as the mean ± SEM. *P < 0.05 versus saline. Scale bar, 200 um.
Figure 7
Figure 7
Altered ghrelin transport in the mediobasal hypothalamus of overfed pups. (A) Representative images showing tanycytic processes and cell bodies labeled by fluorescent ghrelin (25 nmoles per animal; green on left panel, white on right panel) 5 min after intravenous injection. Left panel, PECAM-immunoreactive pituitary portal blood vessels are shown in red. Right panel, GFAP-immunoreactive astrocytes are shown in red. (B) Representative images of clathrin immunoreactivity (green) in tanycytes treated in vitro for 15 min with fluorescent ghrelin (50 nM, red). (D) Representative western blots and quantification of ghrelin and clathrin in immunoprecipitated (IPP) clathrin-coated vesicles from tanycytes treated in vitro for 15 min with vehicle or ghrelin (1 μg/ml). (D) Representative western blots and quantification of ghrelin in mediobasal hypothalamic explants from P14 normal litter (NL) and small litter (SL) mice 45 min after intraperitoneal administration of ghrelin (2 mg/kg) or saline (n = 4 per group). Values are shown as the mean ± SEM. *P < 0.05 versus NL saline; #P < 0.05 versus NL ghrelin. Scale bar, 10 um.
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