| 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
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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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| 11. |
- Hedjazifar, Shahram, 1975, et al.
(författare)
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The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:3, s. 331-341
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Tidskriftsartikel (refereegranskat)abstract
- The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.
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| 12. |
- Hoffmann, Jenny M, et al.
(författare)
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BMP4 gene therapy enhances insulin sensitivity but not adipose tissue browning in obese mice
- 2020
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 32, s. 15-26
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Bone morphogenetic protein 4 (BMP4) adeno-associated viral vectors of serotype 8 (AAV8) gene therapy targeting the liver prevents the development of obesity in initially lean mice by browning the large subcutaneous white adipose tissue (WAT) and enhancing energy expenditure. Here, we examine whether this approach could also reduce established obesity. Methods: Dietary-induced obese C57BL6/N mice received AAV8 BMP4 gene therapy at 17-18 weeks of age. They were kept on a high-fat diet and phenotypically characterized for an additional 10-12 weeks. Following termination, the mice underwent additional characterization in vitro. Results: Surprisingly, we observed no effect on body weight, browning of WAT, or energy expenditure in these obese mice, but whole-body insulin sensitivity and glucose tolerance were robustly improved. Insulin signaling and insulin-stimulated glucose uptake were increased in both adipose cells and skeletal muscle. BMP4 also decreased hepatic glucose production and reduced gluconeogenic enzymes in the liver, but not in the kidney, in addition to enhancing insulin action in the liver. Conclusions: Our findings show that BMP4 prevents, but does not reverse, established obesity in adult mice, while it improves insulin sensitivity independent of weight reduction. The BMP antagonist Noggin was increased in WAT in obesity, which may account for the lack of browning. (C) 2019 The Author(s). Published by Elsevier GmbH.
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| 13. |
- Hoffmann, Jenny M, et al.
(författare)
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BMP4 Gene Therapy in Mature Mice Reduces BAT Activation but Protects from Obesity by Browning Subcutaneous Adipose Tissue.
- 2017
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Ingår i: Cell reports. - : Elsevier BV. - 2211-1247. ; 20:5, s. 1038-1049
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Tidskriftsartikel (refereegranskat)abstract
- We examined the effect of Bone Morphogenetic Protein 4 (BMP4) on energy expenditure in adult mature mice by targeting the liver with adeno-associated viral (AAV) BMP4 vectors to increase circulating levels. We verified the direct effect of BMP4 in inducing a brown oxidative phenotype in differentiating preadipocytes invitro. AAV-BMP4-treated mice display marked browning of subcutaneous adipocytes, with increased mitochondria and Uncoupling Protein 1 (UCP1). These mice are protected from obesity on a high-fat diet and have increased whole-body energy expenditure, improved insulin sensitivity, reduced liver fat, and reduced adipose tissue inflammation. On a control diet, they show unchanged body weight but improved insulin sensitivity. In contrast, AAV-BMP4-treated mice showed beiging of BAT with reduced UCP1, increased lipids, and reduced hormone-sensitive lipase (HSL). Thus, BMP4 exerts different effects on WAT and BAT, but the overall effect is to enhance insulin sensitivity and whole-body energy expenditure by browning subcutaneous adipose tissue.
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| 14. |
- Khatib Shahidi, Roxana, et al.
(författare)
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Adult mice are unresponsive to AAV8-Gremlin1 gene therapy targeting the liver
- 2021
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective Gremlin 1 (GREM1) is a secreted BMP2/4 inhibitor which regulates commitment and differentiation of human adipose precursor cells and prevents the browning effect of BMP4. GREM1 is an insulin antagonist and serum levels are high in type 2 diabetes (T2D). We here examined in vivo effects of AAV8 (Adeno-Associated Viral vectors of serotype eight) GREM 1 targeting the liver in mature mice to increase its systemic secretion and also, in a separate study, injected recombinant GREM 1 intraperitoneally. The objective was to characterize systemic effects of GREM 1 on insulin sensitivity, glucose tolerance, body weight, adipose cell browning and other local tissue effects. Methods Adult mice were injected with AAV8 vectors expressing GREM1 in the liver or receiving regular intra-peritoneal injections of recombinant GREM1 protein. The mice were fed with a low fat or high fat diet (HFD) and followed over time. Results Liver-targeted AAV8-GREM1 did not alter body weight, whole-body glucose and insulin tolerance, or adipose tissue gene expression. Although GREM1 protein accumulated in liver cells, GREM1 serum levels were not increased suggesting that it may not have been normally processed for secretion. Hepatic lipid accumulation, inflammation and fibrosis were also not changed. Repeated intraperitoneal rec-GREM1 injections for 5 weeks were also without effects on body weight and insulin sensitivity. UCP1 was slightly but significantly reduced in both white and brown adipose tissue but this was not of sufficient magnitude to alter body weight. We validated that recombinant GREM1 inhibited BMP4-induced pSMAD1/5/9 in murine cells in vitro, but saw no direct inhibitory effect on insulin signalling and pAkt (ser 473 and thr 308) activation. Conclusion GREM1 accumulates intracellularly when overexpressed in the liver cells of mature mice and is apparently not normally processed/secreted. However, also repeated intraperitoneal injections were without effects on body weight and insulin sensitivity and adipose tissue UCP1 levels were only marginally reduced. These results suggest that mature mice do not readily respond to GREMLIN 1 but treatment of murine cells with GREMLIN 1 protein in vitro validated its inhibitory effect on BMP4 signalling while insulin signalling was not altered.
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| 15. |
- Longo, Michele, et al.
(författare)
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Epigenetic modifications of the Zfp/ZNF423 gene control murine adipogenic commitment and are dysregulated in human hypertrophic obesity.
- 2018
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 61:2, s. 369-80
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Tidskriftsartikel (refereegranskat)abstract
- Subcutaneous adipocyte hypertrophy is associated with insulin resistance and increased risk of type 2 diabetes, and predicts its future development independent of obesity. In humans, subcutaneous adipose tissue hypertrophy is a consequence of impaired adipocyte precursor cell recruitment into the adipogenic pathway rather than a lack of precursor cells. The zinc finger transcription factor known as zinc finger protein (ZFP) 423 has been identified as a major determinant of pre-adipocyte commitment and maintained white adipose cell function. Although its levels do not change during adipogenesis, ectopic expression of Zfp423 in non-adipogenic murine cells is sufficient to activate expression of the gene encoding peroxisome proliferator-activated receptor γ (Pparγ; also known as Pparg) and increase the adipogenic potential of these cells. We investigated whether the Zfp423 gene is under epigenetic regulation and whether this plays a role in the restricted adipogenesis associated with hypertrophic obesity.Murine 3T3-L1 and NIH-3T3 cells were used as fibroblasts committed and uncommitted to the adipocyte lineage, respectively. Human pre-adipocytes were isolated from the stromal vascular fraction of subcutaneous adipose tissue of 20 lean non-diabetic individuals with a wide adipose cell size range. mRNA levels were measured by quantitative real-time PCR, while methylation levels were analysed by bisulphite sequencing. Chromatin structure was analysed by micrococcal nuclease protection assay, and DNA-methyltransferases were chemically inhibited by 5-azacytidine. Adipocyte differentiation rate was evaluated by Oil Red O staining.Comparison of uncommitted (NIH-3T3) and committed (3T3-L1) adipose precursor cells revealed that Zfp423 expression increased (p<0.01) in parallel with the ability of the cells to differentiate into mature adipocytes owing to both decreased promoter DNA methylation (p<0.001) and nucleosome occupancy (nucleosome [NUC] 1 p<0.01; NUC2 p<0.001) in the 3T3-L1 compared with NIH-3T3 cells. Interestingly, non-adipogenic epigenetic profiles can be reverted in NIH-3T3 cells as 5-azacytidine treatment increased Zfp423 mRNA levels (p<0.01), reduced DNA methylation at a specific CpG site (p<0.01), decreased nucleosome occupancy (NUC1, NUC2: p<0.001) and induced adipocyte differentiation (p<0.05). These epigenetic modifications can also be initiated in response to changes in the pre-adipose cell microenvironment, in which bone morphogenetic protein 4 (BMP4) plays a key role. We finally showed that, in human adipocyte precursor cells, impaired epigenetic regulation of zinc nuclear factor (ZNF)423 (the human orthologue of murine Zfp423) was associated with inappropriate subcutaneous adipose cell hypertrophy. As in NIH-3T3 cells, the normal ZNF423 epigenetic profile was rescued by 5-azacytidine exposure.Our results show that epigenetic events regulate the ability of precursor cells to commit and differentiate into mature adipocytes by modulating ZNF423, and indicate that dysregulation of these mechanisms accompanies subcutaneous adipose tissue hypertrophy in humans.
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| 16. |
- Ohlsson, Claes, 1965, et al.
(författare)
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Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice.
- 2017
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 313:4
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Tidskriftsartikel (refereegranskat)abstract
- Females are in general more insulin sensitive than males. To investigate if this is a direct effect of sex-steroids (SS) in white adipose tissue (WAT), we developed a male mouse model over expressing the aromatase enzyme, converting testosterone (T) to estradiol (E2), specifically in WAT (Ap2-arom mice). Adipose tissue E2 levels were increased while circulating SS levels were unaffected in male Ap2-arom mice. Importantly, male Ap2-arom mice were more insulin sensitive compared with WT mice and exhibited increased serum adiponectin levels and upregulated expression of Glut4 and Irs1 in WAT. The expression of markers of macrophages and immune cell infiltration was markedly decreased in WAT of male Ap2-arom mice. The adipogenesis was enhanced in male Ap2-arom mice, supported by elevated Pparg expression in WAT and enhanced differentiation of pre-adipocyte into mature adipocytes. In summary, increased adipose tissue aromatase activity reduces adipose tissue inflammation and improves insulin sensitivity in male mice. We propose that estrogen increases insulin sensitivity via a local effect in WAT on adiponectin expression, adipose tissue inflammation, and adipogenesis.
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| 17. |
- Ahluwalia, T. S., et al.
(författare)
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Genome-wide association study of circulating interleukin 6 levels identifies novel loci
- 2021
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 30:5, s. 393-409
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (n(discovery)=52654 and n(replication)=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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| 18. |
- Arner, P., et al.
(författare)
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Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis
- 2011
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Ingår i: PLoS One. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition. CONCLUSIONS/SIGNIFICANCE: Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess.
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| 19. |
- Boesgaard, T. W., et al.
(författare)
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The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients--the EUGENE2 study
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:5, s. 816-20
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: A recent genome-wide association study identified the SLC30A8 rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabetic patients. METHODS: We genotyped SLC30A8 rs13266634 in 846 non-diabetic offspring of type 2 diabetic patients from five different white populations: Danish (n = 271), Finnish (n = 217), German (n = 149), Italian (n = 109) and Swedish (n = 100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity. RESULTS: Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624 +/- 3,197; CT 3,763 +/- 2,674; TT 4,478 +/- 3,032 pmol l(-1) min(-1), mean +/- SD; p = 0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity. CONCLUSIONS/INTERPRETATION: Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.
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| 20. |
- D'Esposito, V., et al.
(författare)
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Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro
- 2012
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 55:10, s. 2811-2822
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes and obesity are associated with increased risk of site-specific cancers. We have investigated whether metabolic alterations at the level of adipose-derived differentiating cells may affect specific phenotypes of breast cancer cells. Growth profiles of breast cancer cell lines were evaluated in co-cultures with differentiated adipocytes or their precursor cells and upon treatment with adipocyte conditioned media. Production and release of cytokines and growth factors were assessed by real-time RT-PCR and multiplex-based ELISA assays. Co-cultures with either differentiated mouse 3T3-L1 or human mammary adipocytes increased viability of MCF-7 cells to a greater extent, when compared with their undifferentiated precursors. Adipocytes cultured in 25 mmol/l glucose were twofold more effective in promoting cell growth, compared with those grown in 5.5 mmol/l glucose, and activated mitogenic pathways in MCF-7 cells. Growth-promoting action was also enhanced when adipocytes were incubated in the presence of palmitate or oleate. Interestingly, 3T3-L1 and human adipocytes released higher amounts of keratinocyte-derived chemokine/IL-8, the protein 'regulated upon activation, normally T expressed, and secreted' (RANTES), and IGF-1, compared with their precursor cells. Their levels were reduced upon incubation with low glucose and enhanced by fatty acids. Moreover, both undifferentiated cells and differentiated adipocytes from obese individuals displayed about twofold higher IGF-1 release and MCF-7 cell growth induction than lean individuals. Finally, inhibition of the IGF-1 pathway almost completely prevented the growth-promoting effect of adipocytes on breast cancer cells. IGF-1 release by adipocytes is regulated by glucose and fatty acids and may contribute to the control of cancer cell growth in obese individuals.
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| 21. |
- Eliasson, Björn, 1959, et al.
(författare)
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Cephalic phase of insulin secretion in response to a meal is unrelated to family history of type 2 diabetes
- 2017
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- The pre-absorptive cephalic phase of insulin secretion is elicited during the first ten min of a meal and before glucose levels rise. Its importance for insulin release during the post-absorptive phase has been well documented in animals but its presence or importance in man has become increasingly controversial. We here examined the presence of an early cephalic phase of insulin release in 31 well matched individuals without (n = 15) or with (n = 16) a known family history of type 2 diabetes (first-degree relatives; FDR). We also examined the potential differences in individuals with or without impaired fasting (IFG) and impaired glucose tolerance (IGT). We here demonstrate that a cephalic phase of insulin secretion was present in all individuals examined and without any differences between control persons and FDR or IFG/IGT. However, the overall importance of the cephalic phase is conjectural since it was unrelated to the subsequent post-absorptive insulin release or glucose tolerance. One of the best predictors of the incremental cephalic phase of insulin release was fasting insulin level and, thus, a relation to degree of insulin sensitivity is likely. In conclusion, an early pre-absorptive and cephalic phase of insulin release is robustly present in man. However, we could not document any relation to family history of Type 2 diabetes nor to the post-absorptive phase and, thus, confirm its importance for subsequent degree of insulin release or glucose tolerance.
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| 22. |
- Graham, T. E., et al.
(författare)
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Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects
- 2006
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Ingår i: N Engl J Med. - 1533-4406. ; 354:24, s. 2552-63
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance. METHODS: We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes. RESULTS: Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated. CONCLUSIONS: RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.
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| 23. |
- Gustafson, Birgit, 1951, et al.
(författare)
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Inflamed Adipose Tissue: A Culprit Underlying the Metabolic Syndrome and Atherosclerosis
- 2007
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Ingår i: Arterioscler Thromb Vasc Biol. - 1524-4636. ; 27
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Tidskriftsartikel (refereegranskat)abstract
- The metabolic syndrome is associated with a dysregulated adipose tissue; in part a consequence of adipose cell enlargement and the associated infiltration of macrophages. Adipose cell enlargement leads to a proinflammatory state in the cells with reduced secretion of adiponectin and with increased secretion of several cytokines and chemokines including interleukin (IL)-6, IL-8, and MCP-1. MCP-1 has been shown to play an important role for the associated recruitment of macrophages into the adipose tissue. The increased release of cytokines leads to an impaired differentiation of the preadipocytes with reduced lipid accumulation and induction of adiponectin, thus promoting ectopic lipid storage. In particular tumor necrosis factor (TNF) alpha, but also IL-6, has been shown to induce these effects in preadipocytes and this is associated with an increased Wnt signaling maintaining the cells in an undifferentiated and proinflammatory state. The proinflammatory state in the adipose tissue also leads to a local insulin resistance including an impaired inhibitory effect of insulin on FFA release. The insulin resistance further supports the proinflammatory state because insulin, by itself, is both antilipolytic and antiinflammatory by antagonizing cytokine-induced activation of STAT signaling.
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| 24. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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Adipose tissue dysfunction is associated with low levels of the novel Palmitic Acid Hydroxystearic Acids
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue dysfunction is considered an important contributor to systemic insulin resistance and Type 2 diabetes (T2D). Recently, a novel family of endogenous lipids, palmitic acid hydroxy stearic acids (PAHSAs), was discovered. These have anti-diabetic and anti-inflammatory effects in mice and are reduced in serum and adipose tissue of insulin resistant humans. In the present study, we investigate if adipose tissue dysfunction is associated with reduced PAHSA levels in human subjects and if PAHSAs influence adipocyte differentiation. Our results show that low expression of adipocyte GLUT4 and adipocyte hypertrophy, markers of adipose tissue dysfunction, are associated with reduced expression of key enzymes for de novo lipogenesis and adipose tissue levels of PAHSAs in human subjects. We also show that GLUT4 is not only a marker of adipose tissue dysfunction, but may be causally related to the observed impairments. PAHSAs may also act locally in the adipose tissue to improve adipogenesis through a mechanism bypassing direct activation of peroxisome proliferator-activated receptor (PPAR.). The discovery of PAHSAs and our current results provide novel insights into positive effects of lipid species in adipose tissue and mechanisms by which dysfunctional adipose tissue is associated with insulin resistance and risk of developing T2D.
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| 25. |
- Hammarstedt, Ann, 1975, et al.
(författare)
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Adipose tissue dysregulation and reduced insulin sensitivity in non-obese individuals with enlarged abdominal adipose cells.
- 2012
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Ingår i: Diabetology & metabolic syndrome. - : Springer Science and Business Media LLC. - 1758-5996. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals. METHOD: 32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements. RESULTS: Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R=0.49, p=0.011) and protein (R=0.51, p=0.004) expression, as well as with circulating adiponectin levels (R=0.46, 0=0.009). In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R=-0.61, 0=0.003) and adipocyte cell size (R=-0.40, p=0.022). Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found between the hypertrophy-associated adipocyte dysregulation and HIF-1alpha in this group of non-obese individuals. CONCLUSIONS: In conclusion, these findings support the concept that it is not obesity per se, but rather metabolic dysfunction of adipose tissue that is associated with systemic insulin resistance and the metabolic syndrome.
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