Abnormalities of the somatotrophic axis in the obese agouti mouse

doi:doi:10.1038/sj.ijo.0803076

Abstract

Objective:

Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A^y/a) mouse as a model of a perturbed melanocortin system.

Design:

Adult obese A^y/a mice were compared to age- and sex-matched wild-type (WT) controls. Weight and body length (nose–anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation.

Results:

Obese A^y/a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A^y/a mice. Obese A^y /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A^y/a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged.

Conclusion:

Increased body length in adult obese A^y/a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis.

Keywords:

growth, melanocortin, agouti, ghrelin, leptin

Abbreviations:

A^y/a mouse, agouti mouse; IGFI, insulin-like growth factor-I; PeVN, periventricular nucleus; Arc, arcuate nucleus; GHRH, growth hormone-releasing hormone; NPY, neuropeptide Y; AgRP, agouti-related protein; -MSH, alpha melancoyte-stimulating hormone; POMC, pro-opiomelanocortin; CNS, central nervous system; GH, growth hormone; GHS-R, growth hormone secretagogue receptor

Original Article