| 1. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice.
- 2006
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 290:2
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Bjursell, Mikael, 1977, et al.
(författare)
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Acutely reduced locomotor activity is a major contributor to Western diet-induced obesity in mice
- 2008
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 294:2
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Tidskriftsartikel (refereegranskat)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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| 3. |
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| 4. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(författare)
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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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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Central NMU signaling in body weight and energy balance regulation: evidence from NMUR2 deletion and chronic central NMU treatment in mice.
- 2009
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 297:3
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the role of the central neuromedin U (NMU) signaling system in body weight and energy balance regulation, we examined the effects of long-term intracerebroventricular (icv) infusion of NMU in C57Bl/6 mice and in mice lacking the gene encoding NMU receptor 2. In diet-induced obese male and female C57BL/6 mice, icv infusion of NMU (8 microg x day(-1) x mouse(-1)) for 7 days decreased body weight and total energy intake compared with vehicle treatment. However, these parameters were unaffected by NMU treatment in lean male and female C57BL/6 mice fed a standard diet. In addition, female (but not male) NMUR2-null mice had increased body weight and body fat mass when fed a high-fat diet but lacked a clear body weight phenotype when fed a standard diet compared with wild-type littermates. Furthermore, female (but not male) NMUR2-null mice fed a high-fat diet were protected from central NMU-induced body weight loss compared with littermate wild-type mice. Thus, we provide the first evidence that long-term central NMU treatment reduces body weight, food intake, and adiposity and that central NMUR2 signaling is required for these effects in female but not male mice.
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| 6. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Ghrelin increases intake of rewarding food in rodents
- 2010
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 15:3, s. 304-311
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether ghrelin action at the level of the ventral tegmental area (VTA), a key node in the mesolimbic reward system, is important for the rewarding and motivational aspects of the consumption of rewarding/palatable food. Mice with a disrupted gene encoding the ghrelin receptor (GHS-R1A) and rats treated peripherally with a GHS-R1A antagonist both show suppressed intake of rewarding food in a free choice (chow/rewarding food) paradigm. Moreover, accumbal dopamine release induced by rewarding food was absent in GHS-R1A knockout mice. Acute bilateral intra-VTA administration of ghrelin increased 1-hour consumption of rewarding food but not standard chow. In comparison with sham rats, VTA-lesioned rats had normal intracerebroventricular ghrelin-induced chow intake, although both intake of and time spent exploring rewarding food was decreased. Finally, the ability of rewarding food to condition a place preference was suppressed by the GHS-R1A antagonist in rats. Our data support the hypothesis that central ghrelin signaling at the level of the VTA is important for the incentive value of rewarding food.
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| 7. |
- Bjursell, Mikael, 1977, et al.
(författare)
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Deletion of Gpr55 Results in Subtle Effects on Energy Metabolism, Motor Activity and Thermal Pain Sensation
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non-cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed states. We therefore generated male mice deficient in the gene coding for the cannabinoid/lysophosphatidylinositol (LPI) receptor Gpr55 and characterized them under normal dietary conditions as well as during high energy dense diet feeding followed by challenge with the CB1 receptor antagonist/GPR55 agonist rimonabant. Gpr55 deficient male mice (Gpr55 KO) were phenotypically indistinguishable from their wild type (WT) siblings for the most part. However, Gpr55 KO animals displayed an intriguing nocturnal pattern of motor activity and energy expenditure (EE). During the initial 6 hours of the night, motor activity was significantly elevated without any significant effect observed in EE. Interestingly, during the last 6 hours of the night motor activity was similar but EE was significantly decreased in the Gpr55 KO mice. No significant difference in motor activity was detected during daytime, but EE was lower in the Gpr55 KO compared to WT mice. The aforementioned patterns were not associated with alterations in energy intake, daytime core body temperature, body weight (BW) or composition, although a non-significant tendency to increased adiposity was seen in Gpr55 KO compared to WT mice. Detailed analyses of daytime activity in the Open Field paradigm unveiled lower horizontal activity and rearing time for the Gpr55 KO mice. Moreover, the Gpr55 KO mice displayed significantly faster reaction time in the tail flick test, indicative of thermal hyperalgesia. The BW-decreasing effect of rimonabant in mice on long-term cafeteria diet did not differ between Gpr55 KO and WT mice. In conclusion, Gpr55 deficiency is associated with subtle effects on diurnal/nocturnal EE and motor activity behaviours but does not appear per se critically required for overall metabolism or behaviours.
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| 8. |
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| 9. |
- Bjursell, Mikael, 1977
(författare)
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Growth Hormone and Melanin-Concentrating Hormone receptor in the regulation of energy balance and metabolism
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Energy homeostasis ? the balance of energy intake, expenditure, and storage ? is controlled by autonomic regulation originating in the hypothalamus and the brain stem, which receive input from the periphery. Upon receiving signals from the periphery, centres in the central nervous system (CNS) react through endocrine or neuronal responses to maintain a steady balance. Growth hormone (GH) and melanin-concentrating hormone (MCH) act in the CNS to influence the energy balance and may be connected to the peripheral signals ghrelin and leptin. The overall aim of this thesis was to investigate how these different hormonal systems interact. To investigate the metabolic role of GH in the CNS, transgenic mice that overexpress bovine GH in the CNS (GFAP-bGH) were studied. GFAP-bGH mice have higher food intake and body weight and are obese compared with wild-type (WT) mice. Moreover, GFAP-bGH mice had hyperinsulinemia, pancreas islet hyperplasia, and dyslipidemia, but no changes in energy expenditure were observed. Thus, GH is an orexigenic signal in the CNS that leads to obesity and alters insulin and blood lipid profiles. Mice deficient in the gene encoding GHr (GHr KO) were injected in the CNS with ghrelin to study whether the orexigenic signal from ghrelin is dependent on functional GH signalling. The stimulatory effect of ghrelin on food intake was blunted in GHr KO mice, which suggests that the effects of ghrelin on food intake involve the central GH/GHr system. Furthermore, GHr KO mice were growth retarded and obese with higher leptin and corticosterone levels, low insulin and glucose levels and altered circulating lipids. Functional GH signalling is thus required for normal carbohydrate metabolism and lipid biology. The orexigenic neuropeptide MCH may also be involved in ghrelin-induced food intake and GH secretion. Food intake of mice that were deficient in the gene encoding MCHr (MCHr KO) and were injected in the CNS with ghrelin was similar to that of ghrelin injected WT mice, which suggests that MCHr is not required for the stimulating effect of ghrelin on food intake. But ghrelin had no effect on pituitary GH expression in MCHr KO mice, which suggests that MCHr is involved in ghrelin-mediated GH expression. Furthermore, MCHr is important for the acute effect of intracerebroventricular ghrelin on serum insulin but not on corticosterone levels. Thus, functional MCHr is required for the effects of ghrelin on GH expression and insulin secretion. Since leptin and MCH act in common pathways in the hypothalamus to regulate energy balance, leptin-deficient MCHr KO (MCHr KO ob/ob) mice were studied to investigate the importance of MCHr on the phenotype of ob/ob mice. MCHr KO ob/ob mice were similar to ob/ob mice concerning body weight, food intake, hepatic steatosis, blood lipid profile, and energy expenditure. But normal glucose tolerance and markedly reduced insulin levels were observed in MCHr KO ob/ob mice, indicating improved insulin sensitivity. MCHr KO ob/ob mice had higher locomotor activity, improved core body temperature regulation, and reduced corticosterone levels. Thus, MCHr may be involved in direct or secondary signalling cascades that lead to changes in insulin sensitivity, locomotor activity, and blood serum parameters. In conclusion, GH and MCHr play important roles in the CNS in regulating energy balance, including effects on food intake, body weight, obesity, and circulating endocrine signals.
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| 10. |
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