Endocrine Abstracts (2004) 7 OC12

Alterations of the somatotrophic axis in the obese agouti (Ay/a) mouse

NM Martin1, PA Houston2, M Patterson1, DF Carmignac3, MA Ghatei1, SR Bloom1 & CJ Small1

1Department of Metabolic Medicine, Imperial College, London, UK; 2Deaprtment of Neuroendocrinology, Imperial College, London, UK; 3Department of Molecular Neuroendocrinology, National Institiute for Medical Research, London, UK.

In addition to obesity, models of abnormal hypothalamic melanocortin signalling display increased linear growth, although the mechanism remains unclear. We have studied the somatotrophic axis in the obese agouti (Ay/a) mouse (male, 12-14 weeks), as a model of an altered melanocortin system. Somatotrophic hormones were measured by radioimmunoassay and hypothalamic neuropeptide expression studied by in situhybridisation.

Obese Ay/a mice were significantly heavier and longer than age-matched wild-type (WT) controls. Plasma insulin-like growth factor (IGF-I) was increased in obese Ay/a mice (463.7 plus/minus 17.5 [Ay/a] vs. 360.2 plus/minus 20.0 nanogrammes per millilitre [WT], P<0.0005), with non-significant increases in plasma and pituitary growth hormone (GH). Consistent with increased adiposity, obese Ay/a mice were hyperleptinaemic (26.6 ± 4.1 [Ay/a] vs. 5.3 plus/minus 0.5 nanogrammes per millilitre [WT], P<0.001). Plasma ghrelin, stomach ghrelin peptide content and stomach ghrelin mRNA expression were all significantly reduced in obese Ay/a mice.

Somatostatin (SRIF) neurones in the hypothalamic periventricular (PeVN) nucleus inhibit GH secretion. PeVN SRIF mRNA expression was reduced in obese Ay/a mice, although this was non-significant (3212.0 plus/minus 495.8 [Ay/a] vs. 6253.5 plus/minus 2169.4. integrated OD units [WT]). Arcuate nucleus (Arc) growth hormone releasing hormone (GHRH) neurones stimulate GH release, yet Arc GHRH mRNA levels were unchanged. Arc neuropeptide Y (NPY) neurones inhibit the somatotrophic axis by stimulating PeVN SRIF neurones. Interestingly, Arc NPY mRNA expression was reduced by 50 percent in obese Ay/a mice (3047.1 plus/minus 589.3 [Ay/a ] vs. 6011.2 ± 819.2 integrated OD units [WT], P<0.01).

Leptin may inhibit PeVN SRIF neurones both directly and indirectly, via Arc NPY neurones, since both neuronal populations express the active form of the leptin receptor. This inhibition would in turn stimulate plasma GH and IGF-I. Thus, in models of an abnormal melanocortin system, leptin may co-ordinate increased linear growth via altered hypothalamic NPY and hence, SRIF signalling.

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