Metabolic and Behavioural Phenotypes in Nestin-Cre Mice Are Caused by Hypothalamic Expression of Human Growth Hormone.
The Nestin-Cre driver mouse line has mild hypopituitarism, reduced body weight, a metabolic phenotype and reduced anxiety. Although several causes have been suggested, a comprehensive explanation is still lacking. In this study we examined the molecular mechanisms leading to this compound phenotype. Upon generation of the Nestin-Cre mice, the human growth hormone (hGH) minigene was inserted downstream of the Cre recombinase to ensure efficient transgene expression. As a result, hGH is expressed in the hypothalamus. This results in the auto/paracrine activation of the GH receptor as demonstrated by the increased phosphorylation of signal transducer and activator of transcription 5 (STAT5) and reduced expression of growth hormone releasing hormone (Ghrh). Low Ghrh levels cause hypopituitarism consistent with the observed mouse growth hormone (mGH) deficiency. mGH deficiency caused reduced activation of the GH receptor and hence reduced phosphorylation of STAT5 in the liver. This led to decreased levels of hepatic Igf-1 mRNA and consequently postnatal growth retardation. Furthermore, genes involved in lipid uptake and synthesis, such as CD36 and very low-density lipoprotein receptor were upregulated, resulting in liver steatosis. In conclusion, this study demonstrates the unexpected expression of hGH in the hypothalamus of Nestin-Cre mice which is able to activate both the GH receptor and the prolactin receptor. Increased hypothalamic GH receptor signaling explains the observed hypopituitarism, reduced growth and metabolic phenotype of Nestin-Cre mice. Activation of either receptor is consistent with reduced anxiety.
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
Jeroen
J
Declercq
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
Bas
B
Brouwers
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
Vincent P E G
VP
Pruniau
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
Pieter
P
Stijnen
Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
Geoffroy
G
de Faudeur
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
Krizia
K
Tuand
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
Sandra
S
Meulemans
Laboratory for the Research of Degenerative Diseases, KU Leuven, Leuven 3000, Belgium.
Lutgarde
L
Serneels
Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
Anica
A
Schraenen
Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
Frans
F
Schuit
Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
John W M
JW
Creemers
D000818:Animals; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064231:Nestin / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
D064231:Nestin; D012333:RNA, Messenger; D011973:Receptors, LDL; D050799:STAT5 Transcription Factor; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; C045073:Cre recombinase; D019426:Integrases