Regulation of insulin-like growth factor-l and binding protein-3 expression in oMtla-oGH transgenic mice

Chow, Jesse C.; Murray, James D.; Pomp, Daniel; Baldwin, R.L.; Calvert, C. C.; Oberbauer, Anita M.

doi:10.1007/bf01974091

Cited by 16 publications

(11 citation statements)

References 36 publications

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“…Transgene activation (provision of zinc sulfate) results in a 10-30-fold enhancement of circulating GH levels (Shanahan et al, 1989;Oberbauer et al, 1992), while inactivation (removal of zinc sulfate) leads to a return to basal levels within 24 h (Shanahan et al, 1989). In addition, Chow et al (1994) have shown that activation of the oMTla-oGH transgene results in nearly a fourfold increase in plasma IGF-I levels, while levels return to control values following transgene inactivation. Thus, the oMTla-oGH line provides a model to study effects of chronically elevated levels of circulating GH as well as the consequences of removal of this stimulus.…”

Section: Discussionmentioning

confidence: 94%

“…While the transgene remains activated, an overall antilipogenic environment would predominate due to elevated GH. However, upon inactivation of the transgene and, presumably, a return to basal levels of GH (Shanahan et al, 1989;Chow et al, 1994), the enhanced population of adipocytes would respond by filling with triacylglycerol droplets, creating an environment of fat deposition, and eventually leading to the observed state of obesity. No evidence exists to date showing differentiation of preadipocyte cells by GH in vivo; hence this explanation is speculative, yet intriguing as it may present a model for in vivo study of the effects of GH on the undifferentiated adipocyte population.…”

Section: Discussionmentioning

confidence: 97%

“…Serum oGH levels in activated oMTla-oGH mice average 120.7ngm1-1 as compared to 3.9 ngm1-1 for non-transgenic control mice (Oberbauer et al, 1992); transgenic mice not stimulated with zinc sulfate have approximately 20-fold lower circulating oGH than the activated transgenics (Shanahan et al, 1989). Additionally, activated transgenies averaged 615ngm1-1 plasma IGF-I levels as compared to 158.8ngm1-1 for non-transgenic control mice (Chow et al, 1994); following transgene inactivation, IGF-I levels fell to 162.6ngm1-1 (Chow et al, 1994).…”

Section: Origin and Husbandry Of Micementioning

confidence: 92%

“…Yet when exogenous zinc is withdrawn, circulating GH returns to basal levels within 24 h (Shanahan et al, 1992). In addition, levels of IGF-I and IGF-1 binding protein 3 also return to basal following oMTla-oGH transgene inactivation (Chow et al, 1994). This ability to temporally control overexpression of GH is unique to the oMTla-oGH line and enables these transgenic mice to act as useful models for studying effects of withdrawal of elevated circulating GH level s on traits of interest.…”

Section: Introductionmentioning

confidence: 96%

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Development of obesity following inactivation of a growth hormone transgene in mice

Pomp

Oberbauer

Murray

1996

Transgenic Research

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Mice with a temporally regulatable ovine metallothionein 1a--ovine growth hormone transgene (oMT1a-oGH) were utilized to study the effects of withdrawal of elevated circulating levels of growth hormone (GH) on growth and body composition. The transgene was activated from 21-42 days of age by provision of zinc sulfate in the drinking water. At 42 days, mice were allocated to either activated transgenic (remain on zinc sulfate) or inactivated transgenic (removal of zinc sulfate) groups, and to receive either ad libitum or restricted (80-90% of ad libitum) access to feed. Non-transgenic control mice were treated similarly. Body weights and intakes were recorded weekly. Mice were killed at 70 d and epididymal and subcutaneous fat pads, trimmed hind carcass and various organs were weighed. The main findings of this study are: (1) food-restricted mice possessing an activated oMT1a-oGH transgene fail to demonstrate increased growth, but exhibit significantly reduced levels of fat (P < 0.05) relative to all other genotype x feed level combinations; and (2) inactivation of the oMT1a-oGH transgene, following a period of elevated GH levels, leads to development of obesity as evidenced by two to three fold increases in epididymal and subcutaneous fat pad weights (P < 0.01) relative to both activated transgenic and non-transgenic control mice. These large increases in fat deposition also occurred when intake was restricted to 80-90% of ad libitum levels, indicating that metabolic changes independent of intake occur in these inactivated transgenic mice. It is possible that highly elevated production of GH in activated oMT1a-oGH transgenic mice leads to (1) enhanced promotion of preadipocyte differentiation, leading to increased numbers of adipocytes that, upon cessation of oGH production, are available for lipid deposition resulting in obesity, or (2) alterations in production of or responsiveness to insulin, leading to increased fat deposition upon removal of the chronic anti-lipogenic actions of GH. The oMT1a-oGH transgenic mouse line should provide a new genetic model with which to investigate the mechanisms by which growth hormone affects obesity.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Section: Origin and Husbandry Of Micementioning

confidence: 92%

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

Development of obesity following inactivation of a growth hormone transgene in mice

Pomp

Oberbauer

Murray

1996

Transgenic Research

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“…Similarly, a considerable overlap of circulating IGFBP-3 concentrations has been observed between acromegalic patients and healthy subjects (34), although IGFBP-3 is considered a sensitive marker of somatotroph function (35,36). For ovine metallothionein 1a-ovine GH transgenic mice, an increase in serum IGFBP-3 and hepatic IGFBP-3 mRNA expression has been reported as a consequence of heavy metal-induced GH overproduction (37). In the present study, the increase in IGFBP-3, which represents the major pool for IGFs in the circulation (for review, see Ref.…”

Section: Figurementioning

confidence: 99%

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice

Blackburn

Dressendorfer²,

Blum³

et al. 1997

European Journal of Endocrinology

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To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0:05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two-to threefold in B and IB mice (P < 0:001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0:001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory. European Journal of Endocrinology 137 701-708

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Actions of IGF System Proteins from Studies of Transgenic and Gene Knockout Models

D’Ercole¹

1999

The IGF System

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Regulation of insulin-like growth factor-l and binding protein-3 expression in oMtla-oGH transgenic mice

Cited by 16 publications

References 36 publications

Development of obesity following inactivation of a growth hormone transgene in mice

Development of obesity following inactivation of a growth hormone transgene in mice

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice

Actions of IGF System Proteins from Studies of Transgenic and Gene Knockout Models

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