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Neuropharmacology. 2017 Feb;113(Pt A):21-30. doi: 10.1016/j.neuropharm.2016.09.023. Epub 2016 Sep 23.

Early life disruption to the ghrelin system with over-eating is resolved in adulthood in male rats.

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School of Health and Biomedical Sciences, RMIT University, Melbourne, Vic., 3083, Australia. Electronic address:
School of Health and Biomedical Sciences, RMIT University, Melbourne, Vic., 3083, Australia.
Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Vic., 3800, Australia.


Early life overweight is a significant risk factor for developmental programming of adult obesity due to changes in the availability of metabolic factors crucial for the maturation of brain appetite-regulatory circuitry. The appetite-stimulating hormone, ghrelin, has been recently identified as a major regulator of the establishment of hypothalamic feeding pathways. Ghrelin exists in circulation in two major forms, as acylated and des-acylated ghrelin. While most research has focused on acyl ghrelin, the role of neonatal des-acyl ghrelin in metabolic programming is currently unknown. Here we assessed the influences of early life overfeeding on the ghrelin system, including acyl and des-acyl ghrelin's ability to access the hypothalamus in male rats. Our data show that early life overfeeding influences the ghrelin system short-term, leading to an acute reduction in circulating des-acyl ghrelin and increased expression of the growth hormone secretagogue receptor (GHSR) in the arcuate nucleus of the hypothalamus (ARC). These changes are associated with increased neuronal activation in response to exogenous acyl, but not des-acyl, ghrelin in the ARC and the paraventricular nucleus of the hypothalamus (PVN). Interestingly, while we observed no differences in the accessibility of the ARC to acyl or des-acyl ghrelin, less exogenous acyl ghrelin reaches the PVN in the neonatally overfed. Importantly, the influences of neonatal overfeeding on the ghrelin system were not maintained into adulthood. Therefore, while early life overfeeding results in excess body weight and stimulates acute changes in the brain's sensitivity to metabolic signals, this developmental mal-programming is at least partially alleviated in adulthood.


Feeding; Fluorescently-labelled ghrelin; Metabolism; Obesity; Perinatal programming

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