| 11. |
- Sundqvist, Anders, et al.
(author)
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Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7)
- 2005
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 1:6, s. 379-391
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Journal article (peer-reviewed)abstract
- The sterol regulatory element binding protein (SREBP) family of transcription factors controls cholesterol and lipid metabolism. The nuclear forms of these proteins are rapidly degraded by the ubiquitin-proteasome pathway, but the signals and factors required for this are unknown. Here, we identify a phosphodegron in SREBP1a that serves as a recognition motif for the SCF(Fbw7) ubiquitin ligase. Fbw7 interacts with nuclear SREBP1a and enhances its ubiquitination and degradation in a manner dependent on the phosphorylation of T426 and S430 by GSK-3. Fbw7 also degrades nuclear SREBP1c and SREBP2, and inactivation of endogenous Fbw7 results in stabilization of nuclear SREBP1 and -2, enhanced expression of SREBP target genes, enhanced synthesis of cholesterol and fatty acids, and enhanced receptor-mediated uptake of LDL. Thus, our results suggest that Fbw7 may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the SREBP family of transcription factors.
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| 12. |
- Xue, Yuan, et al.
(author)
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Hypoxia-independent angiogenesis in adipose tissues during cold acclimation.
- 2009
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 9:1, s. 99-109
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Journal article (peer-reviewed)abstract
- The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here, we show that exposure of mice to cold led to activation of angiogenesis in both white and brown adipose tissues. In the inguinal depot, cold exposure resulted in elevated expression levels of brown-fat-associated proteins, including uncoupling protein-1 (UCP1) and PGC-1alpha. Proangiogenic factors such as VEGF were upregulated, and endogenous angiogenesis inhibitors, including thrombospondin, were downregulated. In wild-type mice, the adipose tissues became hypoxic during cold exposure; in UCP1(-/-) mice, hypoxia did not occur, but, remarkably, the augmented angiogenesis was unaltered and was thus hypoxia independent. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis and significantly impaired nonshivering thermogenesis capacity. Unexpectedly, VEGFR1 blockage resulted in the opposite effects: increased adipose vascularity and nonshivering thermogenesis capacity. Our findings have conceptual implications concerning application of angiogenesis modulators for treatment of obesity and metabolic disorders.
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| 13. |
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| 14. |
- Berggren, PO, et al.
(author)
-
Rolf Luft (1914-2007) - Obituary
- 2007
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In: CELL METABOLISM. - : Elsevier BV. - 1550-4131. ; 6:3, s. 162-163
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Journal article (other academic/artistic)
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| 15. |
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| 16. |
- Erondu, Ngozi, et al.
(author)
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Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults
- 2006
-
In: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 4:4, s. 275-282
-
Journal article (peer-reviewed)abstract
- Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MIK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.
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| 17. |
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| 18. |
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| 19. |
- Speidel, Dina, et al.
(author)
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CAPS1 and CAPS2 Regulate Stability and Recruitment of Insulin Granules in Mouse Pancreatic beta Cells.
- 2008
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 7:1, s. 57-67
-
Journal article (peer-reviewed)abstract
- CAPS1 and CAPS2 regulate dense-core vesicle release of transmitters and hormones in neuroendocrine cells, but their precise roles in the secretory process remain enigmatic. Here we show that CAPS2(-/-) and CAPS1(+/-);CAPS2(-/-) mice, despite having increased insulin sensitivity, are glucose intolerant and that this effect is attributable to a marked reduction of glucose-induced insulin secretion. This correlates with diminished Ca(2+)-dependent exocytosis, a reduction in the size of the morphologically docked pool, a decrease in the readily releasable pool of secretory vesicles, slowed granule priming, and suppression of second-phase (but not first-phase) insulin secretion. In beta cells of CAPS1(+/-);CAPS2(-/-) mice, the lowered insulin content and granule numbers were associated with an increase in lysosome numbers and lysosomal enzyme activity. We conclude that although CAPS proteins are not required for Ca(2+)-dependent exocytosis to proceed, they exert a modulatory effect on insulin granule priming, exocytosis, and stability.
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| 20. |
- Spiegelman, Bruce M, et al.
(author)
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"The adipocyte: a multifunctional cell".
- 2006
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In: Cell metabolism. - : Elsevier BV. - 1550-4131. ; 4:6, s. 425-7
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Conference paper (peer-reviewed)abstract
- The beautiful Thorskog Castle just north of Göteborg on the Swedish west coast was the venue for the 134th Nobel Symposium, entitled "The Adipocyte: A Multifunctional Cell." For three splendid summer days, some 50 scientists working on various aspects of adipocyte biology convened under the auspices of the Nobel Foundation.
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