Endocrine Abstracts

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 (A^y/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 A^y/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 A^y/a mice (463.7 plus/minus 17.5 [A^y/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 A^y/a mice were hyperleptinaemic (26.6 ± 4.1 [A^y/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 A^y/a mice.

Somatostatin (SRIF) neurones in the hypothalamic periventricular (PeVN) nucleus inhibit GH secretion. PeVN SRIF mRNA expression was reduced in obese A^y/a mice, although this was non-significant (3212.0 plus/minus 495.8 [A^y/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 A^y/a mice (3047.1 plus/minus 589.3 [A^y/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.