INCREASED HYPOTHALAMIC SOMATOSTATIN EXPRESSION IN MICE TRANSGENIC FORBOVINE OR HUMAN GH

Acute studies of GH removal by hypophysectomy or GH replacement in adu lt rats have shown that GH has a positive influence on its hypothalami c inhibitory hormone somatostatin (SRIH). The present study was undert aken to assess the effect of lifelong exposure to elevated GH on the d evelopment and differentiation of SRIH-producing hypothalamic neurons, including comparison of differing GH levels and heterologous species of GH. Expression of somatostatin peptide and mRNA was evaluated using respective immunocytochemistry and in situ hybridization in brains of transgenic mice bearing constructs of either human (hGH) or bovine (b GH) linked to metallothionein (MT) promoter or bGH linked to phosphoen olpyruvate carboxykinase (PEPCK) promoter. Nontransgenic littermates s erved as controls. All transgenic constructs resulted in high levels o f circulating heterologous GH and significantly elevated body weights. Both bGH levels and body weights were higher in PEPCK-bGH than in MT- bGH mice; mean weights were not different between MT-bGH and MT-hGH mi ce. Numbers of SRIH-immunoreactive neurons in the hypophysiotropic per iventricular nucleus (PeN) of transgenic mice showed a two-fold increa se (P < 0.01) relative to control animals; the number of SRIH-positive cells in the medial basal hypothalamus (MBH) was comparable for trans genic and control mice. Total SRIH mRNA in situ hybridization intensit y also showed a two-fold increase (P < 0.05) in the PeN of all transge nic mice compared with controls, and was not elevated in the MBH. The higher levels of GH produced in PEPCK-bGH transgenic mice led to great er weight gain, but not to greater SRIH expression than in other GH-tr ansgenic mice, suggesting that the increased SRIH cell number and mRNA in the PeN of MT-GH-transgenic mice may represent a plateau of maxima l feedback stimulation. The results indicate that lifelong elevated he terologous GH in mice stimulates hypothalamic SRIH expression markedly . It is not known whether this mechanism is direct or indirect via a m ediator of GH such as IGF, but the heterologous GH appears to be speci fic to these hypophysiotropic neurons.