Insulin-Like Growth Factor Binding Protein-6 Transgenic Mice: Postnatal Growth, Brain Development, and Reproduction Abnormalities

Bienvenu, G.; Seurin, Danielle; Grellier, Pascale; Froment, Pascal; Baudrimont, M; Monget, Philippe; Bouc, Yves Le; Babajko, Sylvie

doi:10.1210/en.2003-1196

Cited by 51 publications

(41 citation statements)

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“…resting energy expenditure and the energetic cost of activity, were different between groups and were particularly altered in line 17 mice. This could suggest a defect in sympathetic tone activity, as these mice also displayed hypogonadism [18]. Resting energy expenditure is the sum of basal energy expenditure, meal-induced thermogenesis and non-shivering thermogenesis, while energy expended with activity is the intensity of the activity multiplied by its metabolic cost.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously observed that these IGFBP-6 transgenic mice showed a strong transgene expression in the central nervous system, associated with a 25% decrease in cerebellum size and a 50% decrease in cerebellum GFAP expression [18].…”

Section: Introductionmentioning

confidence: 89%

“…Animals and diet Studies were performed with two lines (16 and 17) of 3-month-old male IGFBP-6 transgenic mice bred in our laboratory [18] or with B6/CBA wild-type mice (Charles River, Grenoble, France). Mice were fed a high-fat diet for up to 3 months (33% lard, 7% corn oil, 6% glucides, 30% proteins; 22,100 kJ/kg; UAR, Villemoisson sur Orge, France).…”

Section: Methodsmentioning

confidence: 99%

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Dysregulation of energy homeostasis in mice overexpressing insulin-like growth factor-binding protein 6 in the brain

et al. 2005

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Aims/hypothesis: IGFs, IGF receptors and IGF binding proteins (IGFBPs) are widely expressed in the central nervous system. To investigate the physiological significance of IGFBP-6 in the brain we established two transgenic mouse lines overexpressing human (h)-IGFBP-6 under the control of glial fibrillary acidic protein promoter. Increasing evidence suggests that insulin/IGF signalling pathways could be implicated in the neuroendocrine regulation of energy homeostasis. We explored the impact of brain IGFBP-6 overexpression on the regulation of food intake and energy balance. Methods: Transgenic mice were fed either a control diet or a high-fat diet for up to 3 months. Glucose and insulin tolerance tests were carried out before and after the diet period. Plasma parameters (insulin, leptin, glucose, NEFAs and triglycerides) were measured, and uncoupling protein 1 (UCP-1) expression was quantified in brown adipose tissue. Oxygen consumption was also measured in both groups. Results: The transgenic mice fed a high-fat diet for 3 months developed obesity, showing increases in plasma leptin, glucose and insulin levels and mild insulin resistance. As compared with wild-type mice, no significant differences were found in the quantity of food intake. However, UCP-1 expression was down-regulated in the brown adipose tissue of the transgenic mice. Conclusions/interpretation: Our results show that brain IGFBP-6 has an impact on the regulation of energy homeostasis. These transgenic h-IGFBP-6 mice may be considered a new tool for studies of the involvement of the brain IGF system in metabolism control and obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

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Dysregulation of energy homeostasis in mice overexpressing insulin-like growth factor-binding protein 6 in the brain

et al. 2005

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“…Furthermore, IGFBP-6 inhibits programmed cell death in non-small cell lung cancer cells . Overexpression of IGFBP-6 inhibits both neuroblastoma growth in vivo (Bienvenu et al, 2004) and proliferation of human bronchial epithelial cells . Therefore, IGFBP-6 exerts differential effects on the regulation of cell metabolism in different cell lines.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

et al. 2009

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Osteoblasts can synthesize the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs), which may either enhance or attenuate IGF-stimulated bone cell proliferation. Since estrogen induced osteoblastic differentiation and proliferation through an estrogen-responsive gene in target cells, we investigated the effects of estrogen on IGFBP-6 expression in the human osteoblastic-like cell line SaOS-2. Expressions of IGFBP-6 protein and mRNA increased 2.8 and 2-fold, respectively, in the presence of 17-β-estradiol (E2) (0.01 to 1 μM) and estrogen receptor (ER) in SaOS-2 cells. On the other hand, E2 induced a 2-fold increase in SaOS-2 cell proliferation. To identify genomic sequences associated with estrogen responsiveness, the 5'-promoter region (-44 to +118) of the IGFBP-6 gene was cloned into a chloramphenicol acetyltransferase (CAT) reporter vector. E2 induced a 3-fold increase in CAT activity in SaOS-2 cells transiently transfected with this construct. Identification of the estrogen-responsive element (ERE) [5'-CCTTCA CCTG-3'] (-9 to +1) in this IGFBP-6 gene promoter region was confirmed using electromobility shift assays and deletion analysis. This functional ERE was important for E2-induced trans-activation of the IGFBP-6 gene.These results demonstrate that E2 exhibits a positive effect on IGFBP-6 gene transcription through estrogen-liganded ER binding to the functional ERE in the IGFBP-6 gene promoter in SaOS-2 cells.

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“…Although an effect on prostate development was not specifically noted, there was a generalized decrease in organ size (DeChiara et al, 1990). Similarly, transgenic mice overexpressing human Igfbp-6 under the control of the GFAP promoter show a significant decrease in body weight (Bienvenu et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

Sonic hedgehog signaling regulates the expression of insulin‐like growth factor binding protein‐6 during fetal prostate development

Lipinski¹,

Cook²,

Barnett³

et al. 2005

Developmental Dynamics

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At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme. Abrogation of Hedgehog signaling disrupts proper prostatic budding, ductal growth, and branching. We now show that Hedgehog signaling regulates the expression of insulin-like growth factor binding protein-6 (Igfbp-6) in the developing mouse prostate. Igfbp-6 is a secreted factor that specifically binds insulin-like growth factor-II (IGF-II), prevents its binding to the IGF-I receptor, and is thought to regulate the activity of IGF-II in growth and differentiation. Igfbp-6 is expressed in both the developing and adult prostate. In the urogenital sinus, Igfbp-6 mRNA colocalized with Ptc1 and Gli1 mRNA in the mesenchyme, while Igfbp-6 protein was found in both the mesenchymal and epithelial layers. Exogenous Shh peptide induced expression of Igfbp-6 in the developing prostate while the chemical inhibitor of Hedgehog signaling, cyclopamine, reduced its expression. These studies show that Igfbp-6 is an actual target of Shh signaling in the urogenital sinus and provide the first evidence for a linkage between the Hedgehog and IGF signaling pathways in prostate development. Developmental Dynamics 233:829 -836, 2005.

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Insulin-Like Growth Factor Binding Protein-6 Transgenic Mice: Postnatal Growth, Brain Development, and Reproduction Abnormalities

Cited by 51 publications

References 50 publications

Dysregulation of energy homeostasis in mice overexpressing insulin-like growth factor-binding protein 6 in the brain

Dysregulation of energy homeostasis in mice overexpressing insulin-like growth factor-binding protein 6 in the brain

Transcriptional activation of insulin-like growth factor binding protein 6 by 17β-estradiol in SaOS-2 cells

Sonic hedgehog signaling regulates the expression of insulin‐like growth factor binding protein‐6 during fetal prostate development

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