Compensatory alterations of insulin signal transduction in liver of growth hormone receptor knockout mice

Dominici, Fernando Pablo; Diaz, G Arostegui; Bartke, Andrzej; Kopchick, JJ; Turyn, Daniel

doi:10.1677/joe.0.1660579

Cited by 107 publications

(92 citation statements)

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“…In fact, the occurrence of fasting hypoglycemia has been demonstrated in GHD children (25) and adults (26). This notion has been further supported by studies using animal models such as dwarf rats (27) and GH receptorknockout mice (28). On the other hand, several researchers have recently reported that insulin resistance occurs in GHD subjects.…”

Section: Discussionmentioning

confidence: 87%

Effects of pair-feeding and growth hormone treatment on obese transgenic rats

Furuhata

Hirabayashi²,

Yonezawa³

et al. 2002

European Journal of Endocrinology

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Background: It has been shown that GH-deficient subjects tend to have fat accumulation. We have produced human GH (hGH) transgenic rats that exhibit low circulating hGH levels and hyperphagia. These rats are also characterized by severe obesity, hyperinsulinemia and hyperlipidemia. Objective: The present study was conducted in order to elucidate how excess caloric intake and impaired GH secretion account for fat accumulation and metabolic abnormalities in the transgenic rats. Design and Methods: The transgenic rats were subjected to either pair-feeding with non-transgenic controls or hGH treatment from 4 to 12 weeks of age, and the effects on fat accumulation and some metabolic parameters were assessed. Results: At the age of 12 weeks, body weight and food intake were greater in transgenic than in control rats by 10% and 27% respectively. The ratio of epididymal white adipose tissue weight to body weight (WAT/BW) was more than three times greater in transgenic than in control rats. Although pair-feeding for 8 weeks decreased body weight, it did not affect the WAT/BW ratio. Treatment with hGH affected neither body weight nor food intake, while it reduced the WAT/BW ratio by 30%. Serum concentrations of triglyceride, free fatty acid, insulin and leptin were all significantly higher in the transgenic than in the control rats. Pair-feeding decreased serum triglyceride, insulin and leptin levels, but not serum free fatty acid levels. On the other hand, hGH treatment decreased only serum leptin concentrations. Conclusions: These results suggest that severe fat accumulation in the transgenic rats mainly resulted from the decreased lipolytic action of GH, while metabolic abnormalities mainly resulted from excess caloric intake.

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Section: Discussionmentioning

confidence: 87%

Effects of pair-feeding and growth hormone treatment on obese transgenic rats

Furuhata

Hirabayashi²,

Yonezawa³

et al. 2002

European Journal of Endocrinology

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“…In a previous study we have used mice lacking GH receptors to investigate the consequences of the absence of GH action on insulin sensitivity and insulin signaling (Dominici et al 2000). As an extension of this study, we have now investigated the effects of combined deficiency of GH and PRL and thyrotropin (TSH) on insulin sensitivity and insulin signaling.…”

Section: Introductionmentioning

confidence: 99%

Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice

Dominici¹,

Hauck²,

Argentino³

et al. 2002

Journal of Endocrinology

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In the present study we have used hypopituitary Ames dwarf mice, which lack GH, prolactin and TSH, to investigate the consequences of the deficiency of these hormones on glucose homeostasis and on the initial components of the insulin signal transduction pathway in the liver. Ames dwarf mice displayed hypersensitivity to insulin since they maintained lower fasting glucose concentrations (73% of control values), had significantly reduced amounts of insulin (58% of control values), and exhibited an increased hypoglycemic response to exogenous insulin. Probably as a result of reduced insulin production, Ames dwarf mice displayed intolerance to glucose. The insulin-stimulated phosphorylation of the insulin receptor (IR) tended to be increased in the liver of Ames dwarf mice, while IR receptor protein content was increased by 38%. Insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 was increased by 61 and 72% respectively, while IRS-1 and IRS-2 protein levels were increased by 76 and 95%. The insulin-stimulated association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 was increased by 28%, but unaltered with IRS-2. Interestingly, while the insulin-stimulated phosphotyrosinederived PI 3-kinase activity was not changed, insulin-stimulated protein kinase B activation was increased by 41% in this tissue. These alterations may account for the insulin hypersensitivity exhibited by these animals. The present findings in long-lived Ames dwarf mice add to the evidence that insulin signaling is importantly related to the regulation of aging and life span.

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“…These mice have a number of striking features that have been recently reviewed [2]. First, they are extremely insulin sensitive [3][4][5][6][7][8][9][10][11][12]. Further, circulating levels of glucose and glucagon are decreased at a young age but normalize with advancing age [6,12].…”

Section: Ghr-/-micementioning

confidence: 99%