Longitudinal Monitoring of Sex-Related in vivo Metabolic Changes in the Brain of Alzheimer's Disease Transgenic Mouse Using Magnetic Resonance Spectroscopy
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Epidemiological studies indicate that the incidence of Alzheimer's disease (AD) is higher in women than in men. There is evidence that changes in metabolites in the brain associated with the development of AD are present earlier than structural brainGH is known to regulate glucose and lipid metabolism as well as body growth. Controversy exists as to whether GH-deficient adults are indeed insulin sensitive or insulin resistant. In GH-deficient animal models, however, no clear observation indicating insulin resistance has been made, while increased insulin sensitivity has been reported in those animals. We have produced human GH (hGH) transgenic rats characterized by low circulating hGH levels and virtually no endogenous rat GH secretion. Although the body length of the transgenic rat is normal, they develop massive obesity and insulin resistance, indicating that the transgenic rat is a good model for the analysis of insulin resistance under GH deficiency. In this study, we have examined how GH deficiency affects the early steps of insulin signaling in the liver of the transgenic rat. Circulating glucose and insulin concentrations were significantly higher in the transgenic rats than in their littermates. In addition, impaired glucose tolerance was observed in the transgenic rat. The amount of insulin receptor was smaller in the liver of the transgenic rat, resulting in decreased tyrosine phosphorylation in response to insulin stimulation. The amounts of insulin receptor substrate-1 and -2 (IRS-1 and -2) and insulin-stimulated phosphorylation of IRSs were also smaller in the transgenic rat. Despite the decrease in tyrosine phosphorylation levels of IRSs being mild to moderate (45% for IRS-1 and 16% for IRS-2), associated phosphatidylinositol 3-kinase (PI3-kinase) activity was not increased by insulin stimulation at all in the transgenic rat. To elucidate whether this discrepancy resulted from the alteration in binding of the p85 subunit of PI3-kinase to phosphotyrosine residues of the IRSs, we determined the amount of p85 subunit in the immunocomplexes with anti-phosphotyrosine antibody. Insulin did not affect the amount of p85 subunit associated with phosphotyrosine in the transgenic rats, while it significantly increased in the controls, indicating that alteration may have occurred at the sites of phosphorylated tyrosine residues in IRSs. These results suggest that GH deficiency in the transgenic rat leads to impairment in at least the early steps of insulin signaling in the liver with a resultant defect in glucose metabolism.
Insulin receptor substrate
Insulin tolerance test
IRS1
Somatropin
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Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P < 0.001) increase in glycosylated hemoglobin, glucose, homeostasis model of insulin resistance, and pro-inflammatory cytokines. Serum insulin, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were significantly (P < 0.001) decreased in diabetic rats. Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P < 0.001) down-regulated in testes of diabetic rats, an effect which was significantly increased after administration of taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis.
Pioglitazone
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SH2-containing inositol 5'-phosphatase 2 (SHIP2) is a 5'-lipid phosphatase hydrolyzing the phosphatidylinositol (PI) 3-kinase product PI(3,4,5)P(3) to PI(3,4)P(2) in the regulation of insulin signaling, and is shown to be increased in peripheral tissues of diabetic C57BL/KSJ-db/db mice. To clarify the impact of SHIP2 in the pathogenesis of insulin resistance with type 2 diabetes, we generated transgenic mice overexpressing SHIP2. The body weight of transgenic mice increased by 5.0% (P < 0.05) compared with control wild-type littermates on a normal chow diet, but not on a high-fat diet. Glucose tolerance and insulin sensitivity were mildly but significantly impaired in the transgenic mice only when maintained on the normal chow diet, as shown by 1.2-fold increase in glucose area under the curve over control levels at 9 months old. Insulin-induced phosphorylation of Akt was decreased in the SHIP2-overexpressing fat, skeletal muscle, and liver. In addition, the expression of hepatic mRNAs for glucose-6-phosphatase and phosphoenolpyruvate carboxykinase was increased, that for sterol regulatory element-binding protein 1 was unchanged, and that for glucokinase was decreased. Consistently, hepatic glycogen content was reduced in the 9-month-old transgenic mice. Structure and insulin content were histologically normal in the pancreatic islets of transgenic mice. These results indicate that increased abundance of SHIP2 in vivo contributes, at least in part, to the impairment of glucose metabolism and insulin sensitivity on a normal chow diet, possibly by attenuating peripheral insulin signaling and by altering hepatic gene expression for glucose homeostasis.
Glucokinase
Carbohydrate Metabolism
Insulin tolerance test
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Differentiation of precursor cells into mature fat cells is accompanied by enhanced expression of insulin-like growth factor (IGF)-I and is stimulated by multiple hormones including growth hormone, glucocorticoids, IGF-I and insulin. We used transgenic mice that overexpress insulin-like growth factor binding protein-1 to investigate the role of IGF-I in the accumulation of fat tissue. In response to a sucrose-enriched diet, transgenic mice gained significantly less body weight and the epididymal fat mass was significantly reduced compared with wild-type mice. The increase in adipocyte size was also significantly reduced in transgenic mice compared with wild-type mice. Fewer colonies were generated from adipose tissue from transgenic mice and the mitogenic response of these cells to IGF-I was significantly reduced compared with those from wild-type mice. Induction of glycerol-3-phosphate dehydrogenase, a measure of adipocyte differentiation, by IGF-I but not insulin, was reduced in preadipocytes from transgenic mice. These data indicate that IGF-I has a critical role in the proliferation of adipocyte precursors, the differentiation of preadipocytes and the development of obesity in response to calorie excess.
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Apolipoprotein A-II (apoA-II) is the second most abundant protein in HDLs. Genetic studies in humans have provided evidence of linkage of the apoA-II gene locus to plasma free fatty acid (FFA) levels and to type 2 diabetes, and transgenic mice overexpressing mouse apoA-II have elevated levels of both FFA and triglycerides. We now show that apoA-II promotes insulin resistance and has diverse effects on fat homeostasis. ApoA-II transgenic mice have increased adipose mass and higher plasma leptin levels than C57BL/6J control mice. Fasting glucose levels were similar between apoA-II transgenic and control mice, but plasma insulin levels were elevated approximately twofold in the apoA-II transgenic mice. Compared with control mice, apoA-II transgenic mice exhibited a delay in plasma clearance of a glucose bolus. Adipose tissue isolated from fasted apoA-II transgenic mice exhibited a 50% decrease in triglyceride hydrolysis compared with adipose tissue from control mice. This is consistent with a normal response of adipose tissue to the increased insulin levels in the apoA-II transgenic mice and may partially explain the increased fat deposition. Skeletal muscle isolated from fasted apoA-II transgenic mice exhibited reduced uptake of 2-deoxyglucose compared with muscles isolated from control mice. Our observations indicate that a primary disturbance in lipoprotein metabolism can result in several traits associated with insulin resistance, consistent with the hypothesis that insulin resistance and type 2 diabetes can, under certain circumstances, be related primarily to altered lipid metabolism rather than glucose metabolism.
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The neuroendocrine effects of human growth hormone (hGH) secretion were studied in adult male mice into which an hGH gene fused with mouse metallothionein 1 (mMT-1) promoter had been introduced. Intact transgenic mice had significantly greater plasma luteinizing hormone (LH) levels than did normal littermate controls. Castration increased LH levels in normal mice but was without effect on plasma LH levels in the transgenic mice. In vitro LH secretion and pituitary LH content were higher in the intact transgenic mice than in intact controls, while there was no significant difference in pituitary LH levels and in vitro LH secretion between the 2 groups of castrate animals. Intact transgenic mice exhibited a greater median eminence (ME) norepinephrine (NE) turnover than control animals, but ME NE turnover did not increase after castration in the transgenic animals as was the case in control mice. Castrate mice expressing the hGH gene had plasma levels of prolactin (PRL) similar to those seen in castrate controls, which was unexpected based on a previous study showing greatly attenuated PRL levels in intact hGH mice when compared to intact controls from the same line. Dopamine (DA) turnover in the ME was not significantly affected by the presence of the hGH gene, suggesting that the difference in plasma PRL levels between normal and transgenic mice is mediated through changes in PRL-regulating factors other than DA. In conclusion, the expression of the mMT-1/hGH hybrid gene in male mice leads to major alterations in LH secretion and lesser changes in PRL secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Median eminence
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Metabolic Effects of Transgenic Melanocyte-Stimulating Hormone Overexpression in Lean and Obese Mice
The proopiomelanocortin-derived peptide, α-MSH, inhibits feeding via melanocortin receptors in the hypothalamus and genetic defects inactivating the melanocortin system have been shown to lead to obesity in experimental animals and humans. To determine whether long-term melanocortinergic activation has significant effects on body weight and composition and insulin sensitivity, transgenic mice overexpressing N-terminal proopiomelanocortin, including α- and γ3-MSH, under the control of the cytomegalovirus-promoter were generated. The transgene was expressed in multiple tissues including the hypothalamus, in which both α-MSH and γ3-MSH levels were increased approximately 2-fold, compared with wild-type controls. Transgene homozygous mice were also crossed with obese leptin receptor-deficient db3J and obese yellow Ay mice. MSH overexpression led to uniform, dose- dependent darkening of coat color. MSH overexpression reduced weight gain and adiposity and improved glucose tolerance in lean male mice. In female transgenic mice, there was no significant effect on body weight, but there was a significant decrease in insulin levels. Obesity was attenuated in obese db3J/db3J male and female mice, but there was no improvement in glucose metabolism. In contrast, the MSH transgene improved glucose tolerance in male Ay mice. These results support the hypothesis that long-term melanocortinergic activation could serve as a potential strategy for anti-obesity and/or antidiabetic therapy.
Proopiomelanocortin
Melanocyte-stimulating hormone
Melanocortin 3 receptor
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Transgenic mice that overexpress the entire glucokinase (GK) gene locus have been previously shown to be mildly hypoglycemic and to have improved tolerance to glucose. To determine whether increased GK might also prevent or diminish diabetes in diet-induced obese animals, we examined the effect of feeding these mice a high-fat high–simple carbohydrate low-fiber diet (HF diet) for 30 weeks. In response to this diet, both normal and transgenic mice became obese and had similar BMIs (5.3 ± 0.1 and 5.0 ± 0.1 kg/m2 in transgenic and nontransgenic mice, respectively). The blood glucose concentration of the control mice increased linearly with time and reached 17.0 ± 1.3 mmol/l at the 30th week. In contrast, the blood glucose of GK transgenic mice rose to only 9.7 ± 1.2 mmol/l at the 15th week, after which it returned to 7.6 ± 1.0 mmol/l by the 30th week. The plasma insulin concentration was also lower in the GK transgenic animals (232 ± 79 pmol/l) than in the controls (595 ± 77 pmol/l), but there was no difference in plasma glucagon concentrations. Together, these data indicate that increased GK levels dramatically lessen the development of both hyperglycemia and hyperinsulinemia associated with the feeding of an HF diet.
Glucokinase
Hyperinsulinemia
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