| 1. |
- Andersson, Christian X, 1973, et al.
(författare)
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Inflamed adipose tissue, insulin resistance and vascular injury
- 2008
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Ingår i: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:8, s. 595-603
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall.
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| 2. |
- Grünberg, John, 1985, et al.
(författare)
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Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance.
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity.
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| 3. |
- Grunberg, J. R., et al.
(författare)
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CCN5/WISP2 and metabolic diseases
- 2018
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Ingår i: Journal of Cell Communication and Signaling. - : Springer Science and Business Media LLC. - 1873-9601 .- 1873-961X. ; 12:1, s. 309-318
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and type 2 diabetes increase worldwide at an epidemic rate. It is expected that by the year 2030 around 500 million people will have diabetes; predominantly type 2 diabetes. The CCN family of proteins has become of interest in both metabolic and other common human diseases because of their effects on mesenchymal stem cell (MSCs) proliferation and differentiation as well as being important regulators of fibrosis. We here review current knowledge of the WNT1 inducible signaling pathway protein 2 (CCN5/WISP2). It has been shown to be an important regulator of both these processes through effects on both the canonical WNT and the TGF ss pathways. It is also under normal regulation by the adipogenic commitment factor BMP4, in contrast to conventional canonical WNT ligands, and allows MSCs to undergo normal adipose cell differentiation. CCN5/WISP2 is highly expressed in, and secreted by, MSCs and is an important regulator of MSCs growth. In a transgenic mouse model overexpressing CCN5/WISP2 in the adipose tissue, we have shown that it is secreted and circulating in the blood, the mice develop hypercellular white and brown adipose tissue, have increased lean body mass and enlarged hypercellular hearts. Obese transgenic mice had improved insulin sensitivity. Interestingly, the anti-fibrotic effect of CCN5/WISP2 is protective against heart failure by inhibition of the TGF ss pathway. Understanding how CCN5/WISP2 is regulated and signals is important and may be useful for developing new treatment strategies in obesity and metabolic diseases and it can also be a target in regenerative medicine.
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| 4. |
- Grünberg, John, 1985, et al.
(författare)
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The Novel Secreted Adipokine WNT1-Inducible-Signaling Pathway Protein2/Wisp2 is a Mesenchymal Cell Activator of Canonical Wnt
- 2014
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 289:10, s. 6899-6907
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Tidskriftsartikel (refereegranskat)abstract
- WNT1-inducible-signaling pathway protein2/WISP2 is primarily expressed in mesenchymal stem cells, fibroblasts and adipogenic precursor cells. It is both a secreted and cytosolic protein, the latter regulating precursor cell adipogenic commitment and PPARγ induction by BMP4. To examine the effect of the secreted protein, we expressed a full-length and a truncated, non-secreted WISP2 in NIH3T3 fibroblasts. Secreted, but not truncated WISP2, activated the canonical WNT pathway with increased β-CATENIN levels, its nuclear targeting phosphorylation and LRP5/6 phosphorylation. It also inhibited Pparg activation and the effect of secreted WISP2 was reversed by the WNT antagonist DICKKOPF-1. Differentiated 3T3-L1 adipose cells were also target cells where extracellular WISP2 activated the canonical WNT pathway, inhibited Pparg and associated adipose genes and, like WNT3a, promoted partial de-differentiation of the cells and the induction of a myofibroblast phenotype with activation of markers of fibrosis. Thus, WISP2 exerts dual actions in mesenchymal precursor cells; secreted WISP2 activates canonical WNT and maintains the cells in an undifferentiated state while cytosolic WISP2 regulates adipogenic commitment.
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| 5. |
- Gustafson, Birgit, 1951, et al.
(författare)
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BMP4 and BMP antagonists regulate human white and beige adipogenesis.
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 64:5, s. 1670-1681
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Tidskriftsartikel (refereegranskat)abstract
- The limited expandability of subcutaneous adipose tissue, due to reduced ability to recruit and differentiate new adipocytes, prevents its buffering effect in obesity and is characterized by expanded adipocytes (hypertrophic obesity). Bone morphogenetic protein-4 (BMP4) plays a key role in regulating adipogenic precursor cell commitment and differentiation. We found BMP4 to be induced and secreted by differentiated (pre)adipocytes and BMP4 protein was increased in large adipose cells. However, the precursor cells exhibited a resistance to BMP4 due to increased secretion of the BMP inhibitor Gremlin-1 (GREM1). GREM1 is secreted by (pre)adipocytes and is an inhibitor of both BMP4 and BMP7. BMP4 alone, and/or silencing GREM1, increased transcriptional activation of peroxisome proliferator-activated receptor-γ (PPARγ) and promoted the preadipocytes to assume an oxidative beige/brown adipose phenotype including markers of increased mitochondria and PGC1α. Driving white adipose differentiation inhibited the beige/brown markers suggesting the presence of multipotent adipogenic precursor cells. However, silencing GREM1 and/or adding BMP4 during white adipogenic differentiation re-activated beige/brown markers suggesting that increased BMP4 preferentially regulates the beige/brown phenotype. Thus BMP4, secreted by white adipose cells, is an integral feedback regulator of both white and beige adipogenic commitment and differentiation and resistance to BMP4 by GREM1 characterizes hypertrophic obesity.
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| 6. |
- Gustafson, Birgit, 1951, et al.
(författare)
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Inflammation and impaired adipogenesis in hypertrophic obesity in man
- 2009
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Ingår i: Am J Physiol Endocrinol Metab. - 0193-1849. ; 297, s. E999-E1003
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is mainly associated with adipose cell enlargement in adult man (hypertrophic obesity) while the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of BMI, is negatively correlated with whole-body insulin sensitivity. We here review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue including local cellular insulin resistance with reduced IRS-1 and GLUT-4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation; a well-known finding in these individuals and which promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFalpha, but not MCP-1, resistin or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications. Key words: Wnt signaling, TNFalpha, adipose cells, obesity.
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| 7. |
- Gustafson, Birgit, 1951, et al.
(författare)
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Insulin resistance and impaired adipogenesis
- 2015
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Ingår i: Trends in endocrinology and metabolism. - : Elsevier BV. - 1043-2760. ; 26:4, s. 193-200
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Forskningsöversikt (refereegranskat)abstract
- The adipose tissue is crucial in regulating insulin sensitivity and risk for diabetes through its lipid storage capacity and thermogenic and endocrine functions. Subcutaneous adipose tissue (SAT) stores excess lipids through expansion of adipocytes (hypertrophic obesity) and/or recruitment of new precursor cells (hyperplastic obesity). Hypertrophic obesity in humans, a characteristic of genetic predisposition for diabetes, is associated with abdominal obesity, ectopic fat accumulation, and the metabolic syndrome (MS), while the ability to recruit new adipocytes prevents this. We review the regulation of adipogenesis, its relation to SAT expandability and the risks of ectopic fat accumulation, and insulin resistance. The actions of GLUT4 in SAT, including a novel family of lipids enhancing insulin sensitivity/secretion, and the function of bone morphogenetic proteins (BMPs) in white and beige/brown adipogenesis in humans are highlighted.
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| 8. |
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| 9. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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Impaired Adipogenesis and Dysfunctional Adipose Tissue in Human Hypertrophic Obesity
- 2018
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Ingår i: Physiological Reviews. - : American Physiological Society. - 0031-9333 .- 1522-1210. ; 98:4, s. 1911-1941
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Forskningsöversikt (refereegranskat)abstract
- The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor cells. When inadequate, this leads to a hypertrophic expansion of the cells with increased inflammation, insulin resistance, and a dysfunctional prolipolytic tissue. Epi-/genetic factors regulate SAT adipogenesis and genetic predisposition for type 2 diabetes is associated with markers of an impaired SAT adipogenesis and development of hypertrophic obesity also in nonobese individuals. We here review mechanisms for the adipose precursor cells to enter adipogenesis, emphasizing the role of bone morphogenetic protein-4 (BMP-4) and its endogenous antagonist gremlin-1, which is increased in hypertrophic SAT in humans. Gremlin-1 is a secreted and a likely important mechanism for the impaired SAT adipogenesis in hypertrophic obesity. Transiently increasing BMP-4 enhances adipogenic commitment of the precursor cells while maintained BMP-4 signaling during differentiation induces a beige/brown oxidative phenotype in both human and murine adipose cells. Adipose tissue growth and development also requires increased angiogenesis, and BMP-4, as a proangiogenic molecule, may also be an important feedback regulator of this. Hypertrophic obesity is also associated with increased lipolysis. Reduced lipid storage and increased release of FFA by hypertrophic SAT are important mechanisms for the accumulation of ectopic fat in the liver and other places promoting insulin resistance. Taken together, the limited expansion and storage capacity of SAT is a major driver of the obesity-associated metabolic complications.
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| 10. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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WISP2 Regulates Preadipocyte Commitment and PPARgamma Activation by BMP4
- 2013
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Ingår i: Proceedings of the National Academy of Science of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:7, s. 2563-2568
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Tidskriftsartikel (refereegranskat)abstract
- Inability to recruit new adipose cells following weight gain leads to inappropriate enlargement of existing cells (hypertrophic obesity) associated with inflammation and a dysfunctional adipose tissue. We found increased expression of WNT1 inducible signaling pathway protein 2 (WISP2) and other markers of WNT activation in human abdominal s.c. adipose tissue characterized by hypertrophic obesity combined with increased visceral fat accumulation and insulin resistance. WISP2 activation in the s.c. adipose tissue, but not in visceral fat, identified the metabolic syndrome in equally obese individuals. WISP2 is a novel adipokine, highly expressed and secreted by adipose precursor cells. Knocking down WISP2 induced spontaneous differentiation of 3T3-L1 and human preadipocytes and allowed NIH 3T3 fibroblasts to become committed to the adipose lineage by bone morphogenetic protein 4 (BMP4). WISP2 forms a cytosolic complex with the peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activator zinc finger protein 423 (Zfp423), and this complex is dissociated by BMP4 in a SMAD-dependent manner, thereby allowing Zfp423 to enter the nucleus, activatePPARγ, and commit the cells to the adipose lineage. The importance of intracellularWisp2 protein for BMP4-induced adipogenic commitment and PPARγ activationwas verified by expressing a mutant Wisp2 protein lacking the endoplasmic reticulum signal and secretion sequence. Secreted Wnt/Wisp2 also inhibits differentiation and PPARγ activation, albeit not through Zfp423 nuclear translocation. Thus adipogenic commitment and differentiation is regulated by the cross-talk between BMP4 and canonical WNT signaling and where WISP2 plays a key role. Furthermore, they link WISP2 with hypertrophic obesity and the metabolic syndrome.
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