| 1. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Hedonic and incentive signals for body weight control.
- 2011
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Ingår i: Reviews in endocrine & metabolic disorders. - : Springer Science and Business Media LLC. - 1573-2606 .- 1389-9155. ; 12:3, s. 141-51
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Forskningsöversikt (refereegranskat)abstract
- Here we review the emerging neurobiological understanding of the role of the brain's reward system in the regulation of body weight in health and in disease. Common obesity is characterized by the over-consumption of palatable/rewarding foods, reflecting an imbalance in the relative importance of hedonic versus homeostatic signals. The popular 'incentive salience theory' of food reward recognises not only a hedonic/pleasure component ('liking') but also an incentive motivation component ('wanting' or 'reward-seeking'). Central to the neurobiology of the reward mechanism is the mesoaccumbal dopamine system that confers incentive motivation not only for natural rewards such as food but also by artificial rewards (eg. addictive drugs). Indeed, this mesoaccumbal dopamine system receives and integrates information about the incentive (rewarding) value of foods with information about metabolic status. Problematic over-eating likely reflects a changing balance in the control exerted by hypothalamic versus reward circuits and/or it could reflect an allostatic shift in the hedonic set point for food reward. Certainly, for obesity to prevail, metabolic satiety signals such as leptin and insulin fail to regain control of appetitive brain networks, including those involved in food reward. On the other hand, metabolic control could reflect increased signalling by the stomach-derived orexigenic hormone, ghrelin. We have shown that ghrelin activates the mesoaccumbal dopamine system and that central ghrelin signalling is required for reward from both chemical drugs (eg alcohol) and also from palatable food. Future therapies for problematic over-eating and obesity may include drugs that interfere with incentive motivation, such as ghrelin antagonists.
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| 2. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Increase of SUMO-1 expression in response to hypoxia: direct interaction with HIF-1alpha in adult mouse brain and heart in vivo
- 2004
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Ingår i: FEBS letters. - : Wiley. - 0014-5793. ; 569:1-3, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigates the regulation of small ubiquitin-related modifier-1 (SUMO-1) expression in response to hypoxia in adult mouse brain and heart. We observed a significant increase in SUMO-1 mRNAs and proteins after hypoxic stimulation in vivo. Because SUMO-1 interacts with various transcription factors, including hypoxia-inducible factor-1beta (HIF-1beta) in vitro, we not only demonstrated that the HIF-1alpha expression is increased by hypoxia in brain and heart, but also provided evidence that SUMO-1 co-localizes in vivo with HIF-1alpha in response to hypoxia by demonstrating the co-expression of these two proteins in neurons and cardiomyocytes. The specific interaction between SUMO-1 and HIF-1alpha was additionally demonstrated with co-immunoprecipitation. These results indicate that the increased levels of SUMO-1 participate in the modulation of HIF-1alpha function through sumoylation in brain and heart.
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| 3. |
- Skibicka, Karolina P, et al.
(författare)
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Ghrelin directly targets the ventral tegmental area to increase food motivation.
- 2011
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 180, s. 129-37
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin, a circulating orexigenic stomach-derived hormone, has recently been implicated in extra-homeostatic feeding, increasing food reward and food-motivated behavior. The precise target site(s) for ghrelin's effects on food reward have yet to be elucidated. The neurocircuitry underpinning food-motivated behavior involves, in particular, the dopamine cells of the ventral tegmental area (VTA) that project to the nucleus accumbens (NAcc). Ghrelin stimulation in both of these mesolimbic reward areas increases chow intake. Here we sought to determine if ghrelin acts directly within these mesolimbic reward areas to increase food reward/motivation in studies that combine feeding behavior, pharmacology, and neuroanatomy. We found that motivated behavior for a sucrose reward, assessed in an operant conditioning paradigm in rats, was increased when ghrelin was microinjected directly into the VTA but not into the NAcc. By contrast, ghrelin administration to both areas increased the free feeding of chow. Importantly, in a state of overnight food restriction, where endogenous levels of ghrelin are increased, ghrelin receptor (GHS-R1A) blockade in the VTA was sufficient to decrease the motivation to work for a sugar reward. Blockade of the GHS-R1A in VTA or NAcc was not sufficient to reduce fasting-induced chow hyperphagia. Taken together our data identify the VTA but not the NAcc as a direct, necessary, and sufficient target site for ghrelin's action on food motivation.
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| 4. |
- Billig, Håkan, 1955, et al.
(författare)
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Follicular development and apoptosis.
- 2002
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Ingår i: Ernst Schering Research Foundation workshop. - 0947-6075. ; :41, s. 23-41
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Friberg, P. Anders, 1976, et al.
(författare)
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Apoptotic effects of a progesterone receptor antagonist on rat granulosa cells are not mediated via reduced protein isoprenylation.
- 2007
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Ingår i: Molecular reproduction and development. - : Wiley. - 1040-452X .- 1098-2795. ; 74:10, s. 1317-26
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Tidskriftsartikel (refereegranskat)abstract
- Progesterone is a survival factor in rat periovulatory granulosa cells. The mechanisms involved are unclear but progesterone receptor (PGR) antagonists have been shown to inhibit cholesterol synthesis and induce apoptosis. Furthermore, reports suggest that statins induce apoptosis by inhibition of protein isoprenylation. Statins inhibit the rate-limiting step of the cholesterol synthesis, thereby reducing availability of intermediates used for the post-translational isoprenylation process. It has been suggested that PGR antagonists in a similar manner induce apoptosis by decreasing cholesterol synthesis and thereby protein isoprenylation. In this study we hypothesized that the mechanism by which the nuclear PGR antagonist Org 31,710 induces apoptosis in rat periovulatory granulosa cells, is by decreasing cholesterol synthesis and thereby general cell protein isoprenylation. Incubation of isolated granulosa cells with Org 31,710 or simvastatin for 22 hr resulted in increased apoptosis and reduced cholesterol synthesis. However, simvastatin caused a substantial inhibition of cholesterol synthesis after 6 hr in culture without inducing apoptosis. In contrast, Org 31,710 had only a modest effect on cholesterol synthesis after 6 hr while it significantly induced apoptosis. Addition of isoprenylation substrates partially reversed apoptosis induced by simvastatin and to a lesser extent apoptosis induced by Org 31,710. In addition, and in contrast to Org 31,710, simvastatin caused a decrease in isoprenylation of a selected isoprenylation marker protein, the Ras-related protein RAB11. In conclusion, we demonstrate that the PGR antagonist inhibits cholesterol synthesis in granulosa cells but reduced protein isoprenylation is not the mediating mechanism of increased apoptosis as previously hypothesized.
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| 6. |
- Friberg, P. Anders, 1976, et al.
(författare)
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Dominant role of nuclear progesterone receptor in the control of rat periovulatory granulosa cell apoptosis.
- 2009
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Ingår i: Biology of reproduction. - : Oxford University Press (OUP). - 0006-3363 .- 1529-7268. ; 80:6, s. 1160-7
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Tidskriftsartikel (refereegranskat)abstract
- In this study, it was hypothesized that progesterone (P4) acts as a survival factor primarily by actions of the classic nuclear progesterone receptor (PGR) signaling pathway in rat periovulatory granulosa cells. Granulosa cells were isolated from immature female rats primed with equine chorionic gonadotropin/human chorionic gonadotropin and treated in vitro with PGR antagonists. As little as 10 nM of two different PGR antagonists (Org 31710 and RU 486) increased apoptosis measured as caspase 3/7 activity, which was reversed by cotreatment with the progestin R5020. Concurrently, P4 synthesis was decreased. Inhibition of P4 synthesis by cyanoketone similarly induced apoptosis but required greater inhibition of P4 synthesis than that seen after treatment with PGR antagonists. Therefore, the induction of apoptosis by PGR antagonists cannot be explained by decreased P4 synthesis alone. Low concentrations of R5020 also completely reversed the effects of cyanoketone. Inhibition of P4 synthesis was more effective in inducing apoptosis than treatment with PGR antagonists. However, cotreatment with PGR antagonists protected cells from the additional effects of cyanoketone, indicating partial agonist effects of the antagonists and a dominating role for PGR in P4-mediated regulation of apoptosis. Progesterone receptor membrane component 1 (PGRMC1) was expressed in granulosa cells; however, an anti-PGRMC1 antibody did not induce apoptosis in periovulatory granulosa cells. Neither anti-PGRMC1 nor P4 or cyanoketone affected apoptosis of immature granulosa cells. In conclusion, we show that P4 regulates apoptosis in periovulatory granulosa cells by acting via the classic nuclear receptor.
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| 7. |
- Friberg, P. Anders, 1976
(författare)
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Granulosa cell apoptosis: Transcriptional regulation by the nuclear progesterone receptor
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian follicle atresia caused by granulosa cell apoptosis is a central process in normal female physiology. Progesterone has been reported to be a survival factor in granulosa cells at several developmental stages. This thesis focuses on the local functions of progesterone relating to the control of granulosa cell apoptosis during the periovulatory interval. The well-characterized gonadotropin-primed immature rat model was used to generate periovulatory granulosa cells, which were subsequently subjected to serum-free cell culture. The effects mediated by the nuclear progesterone receptor were investigated using two progesterone receptor antagonists, RU 486 (mifepristone) and Org 31710. The transcriptional regulation mediated by the nuclear progesterone receptor was investigated using the Affymetrix microarray technique. Decreased de novo synthesis of cholesterol was found to be one of the major effects of high concentrations of Org 31710. Recent studies have demonstrated that inhibition of cholesterol synthesis results in substrate limitation for post-translational isoprenylation, which has interesting implications for the cellular control of apoptosis. We found that cholesterol synthesis and protein isoprenylation are important factors maintaining granulosa cell survival; however, decreased protein isoprenylation cannot explain the induction of apoptosis by progesterone receptor antagonists. In addition to transcriptional regulation, progesterone also initiates rapid cellular responses that have been suggested to regulate granulosa cell apoptosis. We have demonstrated that Org 31710, which acted on the nuclear progesterone receptor, specifically and reversibly induced apoptosis of periovulatory granulosa cells in vitro. We found no support for any contributing non-genomic signaling of progesterone. Furthermore, we could not corroborate previous reports suggesting rapid effects of progesterone in immature rat follicles. Expanded microarray studies focused on early and late transcriptional effects of low doses of Org 31710. Gene ontology analysis was used to select biologically relevant functional groups for further analyses, including genes involved in apoptosis, reproductive processes, cell adhesion, cell cycle regulation, transcriptional control and angiogenesis. In conclusion, we found that progesterone is a central, survival-promoting regulatory factor that acts via the nuclear progesterone receptor during the periovulatory interval. The identification of novel gene targets of progesterone expands our knowledge of the events that occur in granulosa cells during ovulation and luteinization.
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| 8. |
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| 9. |
- Friberg, P. Anders, 1976, et al.
(författare)
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Transcriptional effects of progesterone receptor antagonist in rat granulosa cells.
- 2010
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Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 315:1-2, s. 121-130
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Tidskriftsartikel (refereegranskat)abstract
- Progesterone, acting via the nuclear progesterone receptor (PGR), reduces apoptosis in periovulatory granulosa cells, and is a likely mediator of the anti-atretic actions of LH. The underlying mechanisms, however, have not been clearly defined. In this study, we sought to identify progesterone-mediated transcriptional changes involved in apoptosis regulation. Granulosa cells from immature, gonadotropin-primed female rats were treated in vitro with 100nM of the PGR antagonist Org 31710. Transcriptional effects were analyzed after 5 and 22h of incubation using microarrays, and the expression of 85 genes was subsequently measured by quantitative PCR. Follow-up experiments focused on genes related to the functional group "apoptosis". We have identified novel, early gene targets of PGR that may be involved in the control of apoptosis and other biologically significant functions in periovulatory granulosa cells. This study expands our knowledge of events that occur during the processes of ovulation and luteinization.
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| 10. |
- Rung, Emilia, 1974, et al.
(författare)
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Depletion of substrates for protein prenylation increases apoptosis in human periovulatory granulosa cells
- 2006
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Ingår i: Molecular reproduction and development. - : Wiley. - 1040-452X .- 1098-2795. ; 73:10, s. 1277-83
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Tidskriftsartikel (refereegranskat)abstract
- Progesterone receptor (PR) stimulation promotes survival in human and rat periovulatory granulosa cells. PR antagonists, Org 31710 and RU 486, both increase apoptosis and decrease cholesterol synthesis in these cells. The decrease in cholesterol synthesis also causes decreased synthesis of other products branching from the cholesterol synthesis pathway, including substrates for protein prenylation. In this study we focus on the link between apoptosis and prenylation in human periovulatory granulosa cells. A decreased cholesterol synthesis and increased apoptosis was verified in experiments with human periovulatory granulosa cells treated with the PR antagonists Org 31710 or RU 486 by measuring caspase-3/7 activity and incorporation of 14C-acetate into cholesterol and progesterone. Correspondingly, specific inhibition of cholesterol synthesis in periovulatory human granulosa cells using HMG-CoA reductase inhibitors (lovastatin or simvastatin) increased apoptosis, measured as caspase-3/7 activity. The increase in apoptosis caused by simvastatin or Org 31710 was partially reversed by addition of the protein prenylation precursors farnesol or geranylgeraniol. In addition, the prenylation inhibitors FTI R115777 and GGTI 2147 increased apoptosis in these cells. In conclusion our data suggest that PR antagonists increase apoptosis and reduce cholesterol synthesis in periovulatory granulosa cells and that the resulting depletion of substrates for protein prenylation may contribute to the increased apoptosis sensitivity.
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