Abnormalities of the somatotrophic axis in the obese agouti mouse.
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.


METHODS
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.


CONCLUSIONS
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.
Martin
N M
NM
Department of Metabolic Medicine, Imperial College at Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
Houston
P A
PA
Patterson
M
M
Sajedi
A
A
Carmignac
D F
DF
Ghatei
M A
MA
Bloom
S R
SR
Small
C J
CJ
D054366:Agouti Signaling Protein; D000818:Animals; D001699:Biometry; D001835:Body Weight; D005753:Gastric Mucosa / Q000378:metabolism; D015870:Gene Expression; D054439:Ghrelin; D006130:Growth Disorders / Q000378:metabolism / Q000503:physiopathology*; D013006:Growth Hormone / Q000097:blood; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D020738:Leptin / Q000097:blood; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D036361:Peptide Hormones / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D013004:Somatostatin / Q000096:biosynthesis / Q000235:genetics
D054366:Agouti Signaling Protein; D054439:Ghrelin; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D036361:Peptide Hormones; D012333:RNA, Messenger; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D009074:Melanocyte-Stimulating Hormones