| 1. |
- Bjursell, Mikael, 1977, et al.
(author)
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Acutely reduced locomotor activity is a major contributor to Western diet-induced obesity in mice
- 2008
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In: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 294:2
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Journal article (peer-reviewed)abstract
- The aim of the present study was to investigate the short- and long-term effects of a high-fat Western diet (WD) on intake, storage, expenditure, and fecal loss of energy as well as effects on locomotor activity and thermogenesis. WD for only 24 h resulted in a marked physiological shift in energy homeostasis, including increased body weight gain, body fat, and energy expenditure (EE) but an acutely lowered locomotor activity. The acute reduction in locomotor activity was observed after only 3–5 h on WD. The energy intake and energy absorption were increased during the first 24 h, lower after 72 h, and normalized between 7 and 14 days on WD compared with mice given chow diet. Core body temperature and EE was increased between 48 and 72 h but normalized after 21 days on WD. These changes paralleled plasma T3 levels and uncoupling protein-1 expression in brown adipose tissue. After 21 days of WD, energy intake and absorption, EE, and body temperature were normalized. In contrast, the locomotor activity was reduced and body weight gain was increased over the entire 21-day study period on WD. Calculations based on the correlation between locomotor activity and EE in 2-h intervals at days 21–23 indicated that a large portion of the higher body weight gain in the WD group could be attributed to the reduced locomotor activity. In summary, an acute and persisting decrease in locomotor activity is most important for the effect of WD on body weight gain and obesity in mice.
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| 2. |
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| 3. |
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| 4. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(author)
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Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
- 2005
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In: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
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Journal article (peer-reviewed)abstract
- It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
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| 5. |
- Egecioglu, Emil, 1977, et al.
(author)
-
Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice.
- 2006
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 290:2
-
Journal article (peer-reviewed)abstract
- We have previously shown that growth hormone (GH) overexpression in the brain increased food intake, accompanied with increased hypothalamic agouti-related protein (AgRP) expression. Ghrelin, which stimulates both appetite and GH secretion, was injected intracerebroventricularly to GHR-/- and littermate control (+/+) mice to determine whether ghrelin's acute effects on appetite are dependent on GHR signaling. GHR-/- mice were also analyzed with respect to serum levels of lipoproteins, apolipoprotein (apo)B, leptin, glucose, and insulin as well as body composition. Central injection of ghrelin into the third dorsal ventricle increased food consumption in +/+ mice, whereas no change was observed in GHR-/- mice. After ghrelin injection, AgRP mRNA expression in the hypothalamus was higher in +/+ littermates than in GHR-/- mice, indicating a possible importance of AgRP in the GHR-mediated effect of ghrelin. Compared with controls, GHR-/- mice had increased food intake, leptin levels, and total and intra-abdominal fat mass per body weight and deceased lean mass. Moreover, serum levels of triglycerides, LDL and HDL cholesterol, and apoB, as well as glucose and insulin levels were lower in the GHR-/- mice. In summary, ghrelin's acute central action to increase food intake requires functionally intact GHR signaling. Long-term GHR deficiency in mice is associated with high plasma leptin levels, obesity, and increased food intake but a marked decrease in all lipoprotein fractions.
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| 6. |
- Olsson, Bob, 1969, et al.
(author)
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Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet
- 2005
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In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:2, s. 920-30
-
Journal article (peer-reviewed)abstract
- It is known that bovine GH (bGH) transgenic mice have increased body mass, insulin resistance, and altered lipoprotein metabolism when fed a normal diet (ND). In this study, the effects of 8 wk of high-fat diet (HFD) were investigated in 6-month-old male bGH mice. Although littermate controls had unchanged energy intake, energy intake was higher in the bGH mice on a HFD than on a low-fat diet. Nevertheless, the bGH mice were resistant to diet-induced weight gain, and only in the bGH mice did the HFD result in increased energy expenditure. Glucose oxidation was higher in the bGH mice compared with littermate controls on both a HFD and ND. In addition, the bGH mice had 0.5 C higher body temperature throughout the day and increased hepatic uncoupling protein 2 expression; changes that were unaffected by the HFD. On a HFD, the effect of bGH overexpression on serum triglycerides and apolipoprotein B was opposite to that on a ND, resulting in higher serum concentrations of triglycerides and apolipoprotein B compared with littermate controls. Increased serum triglycerides were explained by decreased triglyceride clearance. The HFD led to diabetes only in the bGH mice. In conclusion, bGH transgenic mice were resistant to diet-induced obesity despite hyperphagia, possibly due to increased energy expenditure. On a HFD, bGH mice became dyslipidemic and diabetic and thereby more accurately reflect the metabolic situation in acromegalic patients.
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| 7. |
- Améen, Caroline, 1975, et al.
(author)
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Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver.
- 2004
-
In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:6
-
Journal article (peer-reviewed)abstract
- We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-alpha (LXRalpha) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRalpha mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRalpha mRNA but is associated with decreased insulin sensitivity.
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| 8. |
- Johansson, Jan-Ove, 1955, et al.
(author)
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Growth hormone (GH) replacement in GH-deficient adults: a crossover trial comparing the effect on metabolic control, well-being and compliance of three injections per week versus daily injections.
- 2003
-
In: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - 1096-6374. ; 13:6, s. 306-15
-
Journal article (peer-reviewed)abstract
- Growth hormone (GH) replacement therapy regimens in adults using daily subcutaneous (sc) injections may not be optimal with respect to carbohydrate and lipid metabolism. The aim of this study was to compare the efficacy of three times weekly injections with daily sc GH injections in terms of serum IGF-I, IGFBPs, lipoprotein levels, serum bone markers, glucose metabolism, body composition, compliance and well-being. Twenty hypopituitary men, 46-76 years, on a course of stable conventional GH replacement therapy for more than 12 months, were included in a 16-week crossover trial. During the first 8 weeks GH was administered three times per week followed by 8 weeks with daily sc injections with the same weekly dose of GH. Fasting serum samples were collected at baseline and on two consecutive days at the end of each 8-week period. Serum IGF-I and IGFBP-3 concentrations were lower both the first and second morning after the last injection during the period with three injections per week. The second morning after the last GH injection in this period the IGF-I/BP-3 ratio, plasma insulin and FFA were lower whereas IGFBP-1 was increased as compared with values obtained during the period with daily injections. Serum Lp(a) levels, body composition, fat distribution, well-being and compliance were not differently affected by the two treatment regimens. These results suggest that the same weekly dose of GH given as three injections per week reduces serum IGF-I and IGFBP-3 levels without affecting Lp(a) levels. The day-to-day variation in glucose metabolism and FFA serum levels differs considerably between the two modes of GH administration.
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| 9. |
- Lindén, Daniel, 1971, et al.
(author)
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Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48.
- 2002
-
In: The Journal of biological chemistry. - 0021-9258. ; 277:25, s. 23044-53
-
Journal article (peer-reviewed)abstract
- The peroxisome proliferator-activated receptor (PPAR) alpha agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes. These effects resulted in decreased secretion of apoB-100-very low density lipoprotein (VLDL) and an increased secretion of apoB-100 on low density lipoproteins/intermediate density lipoproteins. ApoB-48-VLDL was also replaced by more dense particles. The proteasomal inhibitor lactacystin did not influence the recovery of apoB-100 or apoB-48 in primary rat hepatocytes, indicating that co-translational (proteasomal) degradation is of less importance in these cells. Treatment with WY 14,643 made the recovery of apoB-100 sensitive to lactacystin, most likely reflecting the decreased biosynthesis of triglycerides. The PPAR alpha agonist induced a significant increase in the accumulation of pulse-labeled apoB-100 even after a short pulse (2-5 min). There was also an increase in apoB-100 nascent polypeptides, indicating that the co-translational degradation of apoB-100 was inhibited. However, a minor influence on an early posttranslation degradation cannot be excluded. This decreased co-translational degradation of apoB-100 explained the increased secretion of the protein. The levels of apoB-48 remained unchanged during these pulse-chase experiments, and albumin production was not affected, indicating a specific effect of PPAR alpha agonists on the co-translational degradation of apoB-100. These findings explain the difference in the rate of secretion of the two apoB proteins seen after PPAR alpha activation. PPAR alpha agonists increased the expression and biosynthesis of liver fatty acid-binding protein (LFABP). Increased expression of LFABP by transfection of McA-RH7777 cells increased the secretion of apoB-100, decreased triglyceride biosynthesis and secretion, and increased PPAR alpha mRNA levels. These findings suggest that PPAR alpha and LFABP could interact to amplify the effect of endogenous PPAR alpha agonists on the assembly of VLDL.
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| 10. |
- Movérare-Skrtic, Sofia, et al.
(author)
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Dihydrotestosterone treatment results in obesity and altered lipid metabolism in orchidectomized mice.
- 2006
-
In: Obesity (Silver Spring, Md.). - : Wiley. - 1930-7381 .- 1930-739X. ; 14:4, s. 662-72
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To determine the role of androgen receptor (AR) activation for adipose tissue metabolism. Sex steroids are important regulators of adipose tissue metabolism in men. Androgens may regulate the adipose tissue metabolism in men either directly by stimulation of the AR or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors. Previous studies have shown that estrogen receptor alpha stimulation results in reduced fat mass in men. RESEARCH METHODS AND PROCEDURES: Orchidectomized mice were treated with the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT), 17beta-estradiol, or vehicle. Vo(2), Vco(2), resting metabolic rate, locomotor activity, and food consumption were measured. Furthermore, changes in hepatic gene expression were analyzed. RESULTS: DHT treatment resulted in obesity, associated with reduced energy expenditure and fat oxidation. In contrast, DHT did not affect food consumption or locomotor activity. Furthermore, DHT treatment resulted in increased high-density lipoprotein-cholesterol and triglyceride levels associated with markedly decreased 7alpha-hydroxylase gene expression, indicating decreased bile acid production. DISCUSSION: We showed that AR activation results in obesity and altered lipid metabolism in orchidectomized mice. One may speculate that AR antagonists might be useful in the treatment of obesity in men.
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| 11. |
- Oscarsson, Jan, 1960, et al.
(author)
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Two weeks of daily injections and continuous infusion of recombinant human growth hormone (GH) in GH-deficient adults. II. Effects on serum lipoproteins and lipoprotein and hepatic lipase activity.
- 1996
-
In: Metabolism: clinical and experimental. - 0026-0495. ; 45:3, s. 370-7
-
Journal article (peer-reviewed)abstract
- Recombinant human growth hormone (GH) administered as daily subcutaneous (SC) injections has been shown to affect serum lipoproteins in GH-deficient subjects. However, the effects of continuous infusion of GH on serum lipoproteins have not been investigated in GH-deficient adults. The aim of the present study was to compare effects of daily injections and continuous infusion of GH on lipoprotein metabolism. Recombinant human GH (0.25 U/kg/wk) was administered to nine GH-deficient adult men during a period of 14 days in two different ways, ie, as a daily SC injection at 8:00 PM and as a continuous SC infusion, with 1 month of washout between the treatments. Blood samples and tests were performed in the morning after an overnight fast before the start of GH treatment (day 0) and on day 2 and day 14 of treatment. Abdominal SC adipose tissue lipoprotein lipase (LPL), postheparin plasma LPL, and hepatic lipase (HL) activity were measured 120 minutes after the intake of 100 g glucose. Adipose tissue LPL activity decreased and postheparin plasma HL activity increased after 14 days of GH treatment irrespective of the mode of GH administration, whereas GH treatment had no effect on postheparin plasma LPL activity. Serum triglyceride and very-low-density lipoprotein (VLDL) triglyceride concentrations increased during GH treatment. However, VLDL triglyceride concentrations increased to a greater degree during treatment with daily GH injections than during continuous infusion of GH. Serum apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol concentrations decreased during treatment with daily GH injections, but were not significantly affected by continuous GH infusion. Thus, apo B and LDL cholesterol concentrations were lower after daily GH injections versus continuous GH infusion. Serum lipoprotein(a) [Lp(a)] and apo E concentrations increased during both modes of GH treatment. However, continuous infusion of GH resulted in a more marked increase in Lp(a) and apo E concentrations than daily GH injections. Minor effects were observed on serum apo A-I concentrations but high-density lipoprotein (HDL) cholesterol concentrations were not affected. In conclusion, GH treatment of GH-deficient men influenced adipose tissue LPL and postheparin plasma HL activity, as well as serum lipoprotein concentrations. Moreover, continuous GH infusion and daily GH injections differed with respect to the magnitude of effects on several lipoprotein fractions including VLDL triglycerides, LDL cholesterol, apo B, apo E, and Lp(a) concentrations.
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| 12. |
- Améen, Caroline, 1975, et al.
(author)
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Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver
- 2005
-
In: J Biol Chem. ; 280:2, s. 1224-9
-
Journal article (peer-reviewed)abstract
- Microsomal triglyceride transfer protein (MTP) is rate-limiting in the assembly and secretion of lipoproteins containing apolipoprotein (apo) B. Previously we demonstrated that Wy 14,643 (Wy), a peroxisome proliferator-activated receptor (PPAR) alpha agonist, increases apoB-100 secretion despite decreased triglyceride synthesis. In this study, we sought to determine whether PPARalpha activation increases MTP expression and activity. Treatment with Wy increased hepatic MTP expression and activity in rats and mice and increased MTP expression in primary cultures of rat and mouse hepatocytes. Addition of actinomycin D blocked this increase and the MTP promoter (-136 to +67) containing a conserved DR1 element was activated by Wy, showing that PPARalpha activates transcription of the gene. Wy did not affect MTP expression in the intestine or in cultured hepatocytes from PPARalpha-null mice. A retinoid X receptor agonist (9-cis-retinoic acid), but not a PPARgamma agonist (rosiglitazone), increased MTP mRNA expression in cultured hepatocytes from both wild type and PPARalpha-null mice. In rat hepatocytes incubated with Wy, MTP mRNA levels increased between 6 and 24 h, and MTP protein expression and apoB-100 secretion increased between 24 and 72 h. In conclusion, PPARalpha activation stimulates hepatic MTP expression via increased transcription of the Mtp gene. This effect is paralleled by a change in apoB-100 secretion, indicating that the effect of Wy on apoB-100 secretion is mediated by increased expression of MTP.
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| 13. |
- Bjursell, Mikael, 1977, et al.
(author)
-
Opposing effects of adiponectin receptors 1 and 2 on energy metabolism
- 2007
-
In: DIABETES. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:3, s. 583-593
-
Journal article (peer-reviewed)abstract
- The adipocyte-derived hormone adiponectin regulates glucose and lipid metabolism and influences the risk for developing obesity, type 2 diabetes, and cardiovascular disease. Adiponectin binds to two different seven-transmembrane domain receptors termed AdipoR1 and AdipoR2. To study the physiological importance of these receptors, AdipoR1 gene knockout mice (AdipoR1−/−) and AdipoR2 gene knockout mice (AdipoR2−/−) were generated. AdipoR1−/− mice showed increased adiposity associated with decreased glucose tolerance, spontaneous locomotor activity, and energy expenditure. However, AdipoR2−/− mice were lean and resistant to high-fat diet–induced obesity associated with improved glucose tolerance and higher spontaneous locomotor activity and energy expenditure and reduced plasma cholesterol levels. Thus, AdipoR1 and AdipoR2 are clearly involved in energy metabolism but have opposing effects.
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| 14. |
- Edvardsson, Ulrika, 1967, et al.
(author)
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Insulin and oleic acid increase PPARgamma2 expression in cultured mouse hepatocytes.
- 2006
-
In: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 340:1, s. 111-7
-
Journal article (peer-reviewed)abstract
- Hepatic PPARgamma expression is increased in several animal models of diabetes and obesity, and liver-specific overexpression of PPARgamma induces liver steatosis. The aim of this study was to investigate the regulation of PPARgamma expression in primary mouse hepatocytes. PPARgamma2, but not PPARgamma1, was up-regulated by insulin and to a lesser extent by oleic acid. Insulin increased transcription of the PPARgamma2 gene via phosphatidylinositol 3-kinase activation. The PPARgamma agonist, rosiglitazone, increased PPARgamma2 expression, but not PPARgamma1, only in the presence of insulin. Also aP2 mRNA expression was induced by rosiglitazone to a higher degree in the presence of insulin, while acyl-CoA oxidase was increased independently of insulin. In summary, PPARgamma2 is increased in hepatocytes by oleic acid and insulin. These results may help to understand the regulation of PPARgamma expression in liver, which possibly plays a role in the development of liver steatosis.
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| 15. |
- Edvardsson, Ulrika, 1967, et al.
(author)
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PPARalpha activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes.
- 2006
-
In: Journal of lipid research. - 0022-2275. ; 47:2, s. 329-40
-
Journal article (peer-reviewed)abstract
- Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist Wy14,643 (Wy), hepatic mRNA and protein levels of ADRP as well as hepatic triglyceride content increased. Also in primary mouse hepatocytes, Wy increased ADRP expression and intracellular triglyceride mass. The triglyceride mass increased in spite of unchanged triglyceride biosynthesis and increased palmitic acid oxidation. However, Wy incubation decreased the secretion of newly synthesized triglycerides, whereas apolipoprotein B secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides after Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPARalpha activation, adenovirus-mediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased the secretion of newly synthesized triglycerides. In ADRP-overexpressing cells, Wy incubation resulted in a further decrease in triglyceride secretion. This effect of Wy was not attributable to decreased cellular triglycerides after increased fatty acid oxidation because the triglyceride mass in Wy-treated ADRP-overexpressing cells was unchanged. In summary, PPARalpha activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP.
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| 16. |
- Frick, Fredrik, 1973, et al.
(author)
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Different effects of IGF-I on insulin-stimulated glucose uptake in adipose tissue and skeletal muscle.
- 2000
-
In: American journal of physiology. Endocrinology and metabolism. - 0193-1849. ; 278:4
-
Journal article (peer-reviewed)abstract
- The effect of insulin-like growth factor I (IGF-I) on insulin-stimulated glucose uptake was studied in adipose and muscle tissues of hypophysectomized female rats. IGF-I was given as a subcutaneous infusion via osmotic minipumps for 6 or 20 days. All hypophysectomized rats received L-thyroxine and cortisol replacement therapy. IGF-I treatment increased body weight gain but had no effect on serum glucose or free fatty acid levels. Serum insulin and C-peptide concentrations decreased. Basal and insulin-stimulated glucose incorporation into lipids was reduced in adipose tissue segments and isolated adipocytes from the IGF-I-treated rats. In contrast, insulin treatment of hypophysectomized rats for 7 days increased basal and insulin-stimulated glucose incorporation into lipids in isolated adipocytes. Pretreatment of isolated adipocytes in vitro with IGF-I increased basal and insulin-stimulated glucose incorporation into lipids. These results indicate that the effect of IGF-I on lipogenesis in adipose tissue is not direct but via decreased serum insulin levels, which reduce the capacity of adipocytes to metabolize glucose. Isoproterenol-stimulated lipolysis, but not basal lipolysis, was enhanced in adipocytes from IGF-I-treated animals. In the soleus muscle, the glycogen content and insulin-stimulated glucose incorporation into glycogen were increased in IGF-I-treated rats. In summary, IGF-I has opposite effects on glucose uptake in adipose tissue and skeletal muscle, findings which at least partly explain previous reports of reduced body fat mass, increased body cell mass, and increased insulin responsiveness after IGF-I treatment.
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| 17. |
- Frick, Fredrik, 1973, et al.
(author)
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Hepatic and adipose tissue depot-specific changes in lipid metabolism in Late-onset Obese (LOB) rats.
- 2008
-
In: Lipids. - : Wiley. - 0024-4201 .- 1558-9307. ; 43:4, s. 313-24
-
Journal article (peer-reviewed)abstract
- Transgenic Late-onset OBesity (LOB) rats slowly develop a male-specific, autosomal dominant, obesity phenotype with a specific increase in peri-renal white adipose tissue (WAT) depot and preserved insulin sensitivity (Bains et al. in Endocrinology 145:2666-2679, 2004). To better understand the remarkable phenotype of these rats, the lipid metabolism was investigated in male LOB and non-transgenic (NT) littermates. Total plasma cholesterol (C) levels were normal but total plasma triacylglycerol (TAG) (2.8-fold) and hepatic TAG content (25%) was elevated in LOB males. Plasma VLDL-C and VLDL-TAG levels were higher while plasma apoB levels were 60% lower in LOB males. Increased hepatic TAG secretion explained the increased VLDL levels in LOB males. The hepatic gene expression of FAS, SCD-1, mitochondrial (mt)GPAT, and DGAT2 was up-regulated in both old obese and young non-obese LOB rats. Lipoprotein lipase (LPL) activity in heart and epididymal white adipose tissue (WAT) was unchanged, while LPL activity was increased in peri-renal WAT (30%) and decreased in soleus muscle (40%). Moreover, FAS, SCD-1 and DGAT2 gene expression was increased in peri-renal, but not in epididymal WAT. Basal lipolysis was reduced or unchanged and beta-adrenergic stimulated lipolysis was reduced in WAT from both old obese and young non-obese LOB rats. To summarize, the obese phenotype of LOB male rats is associated with increased hepatic TAG production and secretion, a shift in LPL activity from skeletal muscle to WAT, reduced lipolytic response in WAT depots and a specific increase in expression of genes responsible for fatty acid and TAG synthesis in the peri-renal depot.
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| 18. |
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| 19. |
- Leonsson, Maria, et al.
(author)
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Intima-media thickness in cardiovascularly asymptomatic hypopituitary adults with growth hormone deficiency: relation to body mass index, gender, and other cardiovascular risk factors.
- 2002
-
In: Clinical endocrinology. - 0300-0664. ; 57:6, s. 751-9
-
Journal article (peer-reviewed)abstract
- Increased cardiovascular mortality and carotid atherosclerosis have been observed in hypopituitary patients with untreated GH deficiency (GHD), but results are contradictory and relations to cardiovascular risk factors are not clear. The aim of this study was to investigate intima-media thickness (IMT) in relation to cardiovascular risk factors in adults with GHD.Cross-sectional observational study of 21 men and 13 women with GHD, but without cardiovascular disease, compared to two healthy control groups matched for age, sex and smoking habits. One control group was matched for body mass index (BMI) and the other group was nonobese.IMT of the carotid and femoral arteries, blood pressure, blood samples and anthropometric data.Patients had 12% thicker composite carotid IMT [(IMT of common carotid artery + IMT of bulb)/2] compared to nonobese controls (P = 0.022), but IMT was not different compared to BMI-matched controls. Femoral IMT did not differ between patients and controls. Patients had higher waist : hip ratio (WHR), heart rate, serum triglycerides and fasting insulin concentrations in combination with lower high-density lipoprotein (HDL) cholesterol and smaller low-density lipoprotein (LDL) peak particle size compared to both nonobese and to BMI-matched controls. This cardiovascular risk pattern was more pronounced in female patients than in male patients compared to their gender controls. Carotid IMT was related to age, serum cholesterol, LDL cholesterol and smoking in the patient group. Only age was independently related to carotid IMT in multivariate analysis.These results indicate that high BMI in GH-deficient patients contribute to their increased intima-media thickness. However, several cardiovascular risk factors are present in this patient group independent of their increased BMI, especially in women.
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| 20. |
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| 21. |
- Ljungberg, Anna, 1977, et al.
(author)
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Importance of PPAR alpha for the effects of growth hormone on hepatic lipid and lipoprotein metabolism
- 2007
-
In: Growth Horm IGF Res. - : Elsevier BV. - 1096-6374. ; 17:2, s. 154-64
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Growth hormone (GH) enhances lipolysis in adipose tissue, thereby increasing the flux of fatty acids to other tissues. Moreover, GH increases hepatic triglyceride synthesis and secretion in rats and decreases the action of peroxisome proliferator-activated receptor (PPAR)alpha. PPARalpha is activated by fatty acids and regulates hepatic lipid metabolism in rodents. The aim of this study was to investigate the importance of PPARalpha for the effects of GH on hepatic gene expression and lipoprotein metabolism. DESIGN: Bovine GH was given as a continuous infusion (5mg/kg/day) for 7 days to PPARalpha-null and wild-type (wt) mice. Plasma and liver lipids and hepatic gene expression were measured. In separate experiments, hepatic triglyceride secretion was measured. RESULTS: GH treatment decreased hepatic triglyceride content and increased hepatic triglyceride secretion rate and serum cholesterol levels. Furthermore, GH increased hepatic acylCoA:diacylglycerol acyltransferase (DGAT)2 mRNA levels, but decreased the hepatic mRNA expression of acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase and PPARgamma1. All these GH effects were independent of PPARalpha. However, the effect of GH on Cyp4a10, PPARgamma2, and DGAT1 was different between the genotypes. GH treatment decreased Cyp4a10 mRNA expression in wt mice, but increased the expression in PPARalpha-null mice. In contrast, GH decreased the expression of DGAT1 and PPARgamma2 in PPARalpha-null mice, but not in wt mice. CONCLUSIONS: Most of the effects of GH on lipid and lipoprotein metabolism were independent of PPARalpha. However, GH had unique effects on Cyp4a10, DGAT1, and PPARgamma2 gene expression in PPARalpha-null mice showing cross-talk between GH and PPARalpha signalling in vivo.
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| 22. |
- Oscarsson, Jan, 1960, et al.
(author)
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Effects of growth hormone on lipoprotein lipase and hepatic lipase.
- 1999
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In: Journal of endocrinological investigation. - 0391-4097. ; 22:5 Suppl, s. 2-9
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Research review (peer-reviewed)abstract
- Lipoprotein lipase (LPL) is a key enzyme in the regulation of the flux of fatty acids. LPL hydrolyses triglycerides in chylomicrons and very-low-density lipoproteins (VLDL), forming intermediate- (IDL) and low-density lipoproteins (LDL). Hepatic lipase (HL) is a related enzyme with a more restricted tissue distribution than LPL; HL is mainly engaged in the turnover of IDL and of high-density lipoproteins (HDL). Both enzymes can be released from their endothelial sites by heparin and their activities measured separately in post-heparin plasma (PHP). The PHP-LPL activity decreases in hypophysectomized rats and this effect is reversed by growth hormone (GH) therapy. However, GH seems to have no effect, or an inhibitory effect, on PHP-LPL activity in humans. Muscle and adipose tissues are the main sources of PHP-LPL activity. One week of GH therapy of hypophysectomized rats increases skeletal muscle and heart LPL activity. In this model, GH has little or no effect on LPL activity in adipose tissue. However, GH has been shown to decrease LPL activity in isolated rat adipose tissue. Insulin-like growth factor-I therapy decreases and insulin therapy increases LPL activity in adipose tissue of hypophysectomized rats, whereas these therapies have no effect on LPL activity in muscle tissue. The LPL activity in human adipose tissue is reduced both in vivo and in vitro after administration of GH while the LPL mRNA level is unchanged. The effect of GH on HL activity has been studied in PHP and liver. Several studies in the rat indicate that GH increases PHP-HL and liver HL activity, at least partly at the level of mRNA expression. In humans, GH has been shown to have variable effects on PHP-HL activity; this variability is probably to some extent dependent on different experimental set-ups. Although GH therapy increases hepatic secretion of VLDL, serum triglyceride levels decrease as a result of GH therapy in the hypophysectomized rat. An increase in HL and LPL activity by GH therapy is in line with these findings. In summary, GH is involved in the regulation of both LPL and HL activity but the effects and mechanisms of action of GH in the regulation of LPL and HL activity in different tissues are not yet fully elucidated.
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| 23. |
- Oscarsson, Jan, 1960, et al.
(author)
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GH but not IGF-I or insulin increases lipoprotein lipase activity in muscle tissues of hypophysectomised rats.
- 1999
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In: The Journal of endocrinology. - 0022-0795. ; 160:2, s. 247-55
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Journal article (peer-reviewed)abstract
- Changes in GH secretion are associated with changes in serum lipoproteins, utilisation of fuels and body composition. Since lipoprotein lipase (LPL) is a key enzyme in the regulation of lipid and lipoprotein metabolism, changes in LPL activity may contribute to these effects of GH. The present study was undertaken to investigate the role of GH and the GH-dependent growth factor, IGF-I, in the regulation of LPL in heart, skeletal muscle and adipose tissue. Female rats were hypophysectomised at 50 days of age. One week later, hormonal therapy was commenced. All hypophysectomised rats received l-thyroxine and cortisol. Adipose tissue, the heart, soleus and gastrocnemius muscles were excised after 1 week of hormonal therapy. The effect of insulin injections on adipose tissue and heart LPL activity was also studied. In separate experiments, LPL activity in post-heparin plasma was measured. Hypophysectomy had no effect on adipose tissue LPL activity, whereas activity was reduced in heart, soleus and gastrocnemius muscle tissues. GH treatment had no significant effect on LPL activity in adipose tissue or soleus muscle, but increased the LPL activity in heart and gastrocnemius muscle. GH treatment increased post-heparin plasma LPL activity. Recombinant human IGF-I treatment (1.25 mg/kg per day) markedly reduced LPL activity in adipose tissue, but had no effect in muscle tissues. The effect of IGF-I treatment on adipose tissue LPL was not reflected by a decrease in post-heparin plasma LPL activity. Daily injections of insulin for 7 days increased LPL activity in adipose tissue but had no effect on heart LPL activity. In adipose tissue, LPL mRNA levels tended to decrease as a result of IGF-I treatment. In the muscle tissues, no significant effects of hypophysectomy, GH or IGF-I treatment on LPL mRNA levels were observed.%It is concluded that GH increases heart and skeletal muscle tissue LPL activity, which probably contributes to an increased post-heparin plasma LPL activity. The effect of GH on muscle LPL activity is probably not mediated by IGF-I or insulin. Insulin and IGF-I have opposite effects on LPL activity in adipose tissue.
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| 24. |
- Oscarsson, Jan, 1960, et al.
(author)
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Low dose continuously infused growth hormone results in increased lipoprotein(a) and decreased low density lipoprotein cholesterol concentrations in middle-aged men.
- 1994
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In: Clinical endocrinology. - 0300-0664. ; 41:1, s. 109-16
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Journal article (peer-reviewed)abstract
- Animal studies have shown that slight increases in basal GH concentrations may result in changes in lipoprotein metabolism. Such changes in GH secretion have been observed in physiological and pathophysiological states such as fasting, uncontrolled diabetes and during oestrogen treatment. The aim of this study was to investigate the possible effects of increases in basal plasma GH concentrations on lipoprotein concentrations.Recombinant human growth hormone (rhGH) was given as a continuous subcutaneous infusion in a low dose (0.02 U/kg/day) in an open study.Eight middle-aged (42-59 years) overweight (body mass index: 26.1-33.8 kg/m2) but otherwise healthy men were studied over a period of 14 days.Blood samples were obtained after an over-night fast before and after 2, 7 and 14 days of treatment. Plasma and serum were separated and used for subsequent measurements of hormone and lipoprotein concentrations. On days 0, 7 and 14 of treatment, post-heparin plasma was also obtained for determinations of plasma lipoprotein lipase and hepatic lipase activities. In addition, a hyperinsulinaemic euglycaemic glucose clamp was performed on days 0 and 13 of the study. Fat biopsies from abdominal and gluteal fat depots were obtained for measurement of lipoprotein lipase activities on days 0 and 14 of the study.Serum GH concentrations increased to a steady level of 2-4 mU/l during treatment. Serum insulin-like growth factor-I (IGF-I) concentrations increased throughout the treatment period to twice the pretreatment levels. Plasma insulin and blood glucose concentrations increased on day 2 of treatment. After 7 and 14 days of treatment blood glucose concentrations were not different from pretreatment levels, but plasma insulin concentrations were still elevated. Serum cholesterol and low density lipoprotein (LDL) cholesterol concentrations had decreased after 7 and 14 days of treatment. High density lipoprotein (HDL) cholesterol concentrations were not affected, but very low density lipoprotein (VLDL) cholesterol and triglyceride concentrations increased transiently at day 2 of treatment. Serum apolipoprotein (apo) A-I, apoB and apoE concentrations were not significantly affected. Serum lipoprotein(a) concentrations had increased by days 7 and 14 to 147 and 142% of pretreatment concentrations, respectively. Lipoprotein lipase and hepatic lipase activities in post-heparin plasma, as well as abdominal and gluteal adipose tissue lipoprotein lipase activities, were not affected. There was no significant change in glucose disposal rate estimated from the glucose clamp studies.A low dose infusion of GH results in marked changes in lipoprotein concentrations with a transient increase in VLDL cholesterol and thereafter in a decrease in LDL cholesterol. In addition, this low dose of GH resulted in marked increases in lipoprotein(a) concentrations. The observed effects of GH may partly involve changes in IGF-I and insulin secretion.
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| 25. |
- Persson, Anders I., 1973, et al.
(author)
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Expression of delta opioid receptor mRNA and protein in the rat cerebral cortex and cerebellum is decreased by growth hormone.
- 2003
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In: Journal of neuroscience research. - : Wiley. - 0360-4012 .- 1097-4547. ; 71:4, s. 496-503
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Journal article (peer-reviewed)abstract
- Hormones released from the pituitary have been shown to regulate the expression of different proteins in the central nervous system. We wanted to examine whether peripheral administration of bovine growth hormone (bGH) regulates the expression of delta-opioid receptor (DOR) in the cerebral cortex and cerebellum. Expression of the DOR protein was quantified using Western blot densitometry. DOR mRNA was quantified with a solution hybridization RNase protection assay. Hypophysectomized (Hx) and untreated normal female rats were included in the study. All Hx rats were hormonally treated with cortisol (400 microg/kg/day) and L-thyroxine (10 microg/kg/day) for 19 days. Hypophysectomy resulted in a threefold increase in cerebral cortex and a twofold increase in cerebellum of the DOR protein compared with normal rats. One subgroup of Hx rats received bGH (1 mg/kg body weight) as a daily subcutaneous injection for 19 days. This treatment normalized the levels of DOR protein in the cerebral cortex and cerebellum. Immunohistochemical experiments showed that GH decreased DOR expression especially in layers II-VI in cerebral cortex and in stratum moleculare in cerebellum. Quantification of DOR mRNA by solution hybridization RNase protection assay corresponded to the DOR protein measurements. We conclude that the expression of DORs in cerebral cortex and cerebellum is regulated by GH.
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