Increased hypothalamic somatostatin expression in mice transgenic for bovine or human GH.
Acute studies of GH removal by hypophysectomy or GH replacement in adult rats have shown that GH has a positive influence on its hypothalamic inhibitory hormone somatostatin (SRIH). The present study was undertaken to assess the effect of lifelong exposure to elevated GH on the development 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 (bGH) linked to metallothionein (MT) promoter or bGH linked to phosphoenolpyruvate carboxykinase (PEPCK) promoter. Nontransgenic littermates served as controls. All transgenic constructs resulted in high levels of 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 mice. Numbers of SRIH-immunoreactive neurons in the hypophysiotropic periventricular nucleus (PeN) of transgenic mice showed a two-fold increase (P < 0.01) relative to control animals; the number of SRIH-positive cells in the medial basal hypothalamus (MBH) was comparable for transgenic and control mice. Total SRIH mRNA in situ hybridization intensity also showed a two-fold increase (P < 0.05) in the PeN of all transgenic mice compared with controls, and was not elevated in the MBH. The higher levels of GH produced in PEPCK-bGH transgenic mice led to greater weight gain, but not to greater SRIH expression than in other GH-transgenic mice, suggesting that the increased SRIH cell number and mRNA in the PeN of MT-GH-transgenic mice may represent a plateau of maximal feedback stimulation. The results indicate that lifelong elevated heterologous GH in mice stimulates hypothalamic SRIH expression markedly. It is not known whether this mechanism is direct or indirect via a mediator of GH such as IGF, but the heterologous GH appears to be specific to these hypophysiotropic neurons.
Hurley
D L
DL
Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118.
Bartke
A
A
Wagner
T E
TE
Wee
B E
BE
Phelps
C J
CJ
D000818:Animals; D002417:Cattle; D005260:Female; D015870:Gene Expression; D013006:Growth Hormone / Q000235:genetics*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013004:Somatostatin / Q000235:genetics*
D012333:RNA, Messenger; D013004:Somatostatin; D013006:Growth Hormone; D008668:Metallothionein; D010729:Phosphoenolpyruvate Carboxykinase (GTP)