Abstract
The hypothalamic-pituitary-adrenal (HPA) axis responses to psychological stress are exacerbated in adult female but not male rats made obese due to overfeeding in early life. Ghrelin, traditionally known for its role in energy homeostasis, has been recently recognised for its role in coordinating the HPA responses to stress, particularly by acting directly at the anterior pituitary where the growth hormone secretagogue receptor (GHSR), the receptor for acyl ghrelin, is abundantly expressed. We therefore hypothesised that neonatal overfeeding in female rats would compromise pituitary responsiveness to ghrelin, contributing to a hyperactive central stress responsiveness. Unlike in males where hypothalamic ghrelin signalling is compromised by neonatal overfeeding, there was no effect of early life diet on circulating ghrelin or hypothalamic ghrelin signalling in females, indicating hypothalamic feeding and metabolic ghrelin circuitry remains intact. However, neonatal overfeeding did lead to long-term alterations in the pituitary ghrelin system. The neonatally overfed females had increased neonatal and reduced adult expression of GHSR and ghrelin-O-acyl transferase (GOAT) in the pituitary as well as reduced pituitary responsiveness to exogenous acyl ghrelin-induced adrenocorticotropic hormone (ACTH) release in vitro. These data suggest that neonatal overfeeding dysregulates pituitary ghrelin signalling long-term in females, potentially accounting for the hyper-responsive HPA axis in these animals. These findings have implications for how females may respond to stress throughout life, suggesting the way ghrelin modifies the stress response at the level of the pituitary may be less efficient in the neonatally overfed.
Highlights
Childhood obesity affects more than 40 million people worldwide and is a significant risk factor for adult obesity and myriad co-morbid diseases and disorders, including hypothalamicpituitary-adrenal (HPA) axis dysfunction [1]
There was no difference in neuronal activation after acylated or des-acylated ghrelin in the arcuate nucleus (ARC) (Fig 2A), despite this dose having a significant effect in males [34]
We did see a significant increase in c-Fos in the paraventricular nucleus of the hypothalamus (PVN) in the rats that were given acylated ghrelin (significant effect of drug: F(2,31) = 16.45, p < 0.001; n = 5–6; Fig 2B and 2C), but there was no effect of neonatal overfeeding on this response
Summary
Childhood obesity affects more than 40 million people worldwide and is a significant risk factor for adult obesity and myriad co-morbid diseases and disorders, including hypothalamicpituitary-adrenal (HPA) axis dysfunction [1]. We have previously shown that neonatal overfeeding in a rodent model induces an overweight phenotype that is maintained into adulthood in both males and females [2,3,4], with similar increases in fat mass and circulating leptin between the sexes [2, 4, 5]. Both male and female rats overfed in utero or postnatally show. Females that are overfed in the first three weeks of their lives have increased open arm exploration as adults in the elevated plus maze test for anxiety, indicative of reduced anxiety-like behaviour, but have exacerbated paraventricular nucleus of the hypothalamus (PVN) responses to acute restraint stress; effects that are not seen in males [3]
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