| 1. |
- Andersson, Christian X, 1973, et al.
(author)
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Inflamed adipose tissue, insulin resistance and vascular injury
- 2008
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In: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:8, s. 595-603
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Journal article (peer-reviewed)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. |
- Gustafson, Birgit, 1951, et al.
(author)
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Activation of Canonical Wingless-type MMTV Integration Site Family (Wnt) Signaling in Mature Adipocytes Increases Beta-Catenin Levels and Leads to Cell Dedifferentiation and Insulin Resistance
- 2010
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In: The Journal of Biological Chemistry. - 0021-9258. ; 285, s. 14031-14041
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Journal article (peer-reviewed)abstract
- Canonical Wnt ligands are secreted by several cell types in the adipose tissue. We examined if mature adipocytes can also be target cells and found that canonical Wnt activation by Wnt3a induced a marked dedifferentiation of both 3T3-L1 and human adipocytes. Typical adipogenic markers were reduced while undifferentiated cell markers like Pref-1/Dlk1, Wnt10b, and Gata2 were increased. The cells also became insulin-resistant with impaired upstream insulin signaling and reduced glucose uptake. Wnt3a stabilized B-catenin in the absence of the LRP6 receptor and with maintained axin and Dickkopf-1 protein expression. PPARgamma was repressed and PPARgamma ligands could not restore the adipogenic markers or reduce the B-catenin levels. The dedifferentiated adipocytes expressed the myofibroblast marker alpha-smooth muscle actin and were also susceptible to osteogenic transdifferentiation. These results identify a novel pathway in mature adipose cells that is critical for maintaining the normal adipocyte phenotype and insulin sensitivity.
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| 4. |
- Gustafson, Birgit, 1951, et al.
(author)
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BMP4 and BMP antagonists regulate human white and beige adipogenesis.
- 2015
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 64:5, s. 1670-1681
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Journal article (peer-reviewed)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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| 5. |
- Gustafson, Birgit, 1951, et al.
(author)
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Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes
- 2006
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In: J Biol Chem. - 0021-9258. ; 281:14, s. 9507-16
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Journal article (peer-reviewed)abstract
- Obesity with enlarged fat cells is associated with high local concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) in the adipose tissue. We examined the effects of this inflammatory state on 3T3-L1 preadipocyte development and differentiation to mature adipose cells. Both IL-6 and TNFalpha impaired the normal differentiation pattern and lipid accumulation. However, IL-6 allowed a normal early induction of differentiation with inhibition of Wnt10b and Pref-1, whereas expression of CCAAT/enhancer-binding protein alpha, in contrast to peroxisome proliferator-activated receptor gamma, was markedly reduced. TNFalpha also allowed a normal early induction of differentiation, whereas the terminal differentiation to adipose cells was completely prevented. However, both cytokines induced an inflammatory phenotype of the cells but with different profiles. Remarkably, both IL-6 and TNFalpha maintained and augmented the canonical Wnt signaling associated with low axin and high low density lipoprotein receptor-related protein (LRD), Dishevelled, and beta-catenin levels. TNFalpha, but not IL-6, activated Wnt10b expression, whereas IL-6 increased the apparent phosphorylation of Dishevelled. Thus, both IL-6 and TNFalpha prevent the normal development of preadipocytes to fully differentiated adipose cells and, instead, promote an inflammatory phenotype of the adipocytes. These results provide an explanation as to why obesity and diabetes are associated with both local and systemic inflammation, insulin resistance, and ectopic lipid accumulation.
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| 6. |
- Gustafson, Birgit, 1951
(author)
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Effects of cytokines on preadipocyte differentiation and Wnt signalling
- 2006
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Doctoral thesis (other academic/artistic)abstract
- The relationship between amount of adipose tissue, the Metabolic Syndrome and Type 2 diabetes has been recognized for several years. However, the mechanisms for this remain to be clarified. Not all obese individuals develop insulin resistance or Type 2 diabetes and these perturbations are also seen in non-obese individuals. Adipose cell enlargement is a marker of obesity, but adipocytes have a limited capacity for lipid storage. Adipose cell growth and differentiation are important steps for normal lipid storage. Interestingly, obesity and insulin resistance are associated with an inflamed adipose tissue and infiltration of macrophages. Thus, the cytokine levels are expected to be increased in the adipose tissue under those conditions. This thesis is focused on elucidating the consequences of increased adipose tissue cytokine levels on preadipocyte development and function.We first measured interstitial IL-6 concentrations (Paper I) and found that local IL-6 concentrations in the adipose tissue were markedly higher than in plasma. Interestingly, the interstitial IL-6 concentrations were positively correlated with adipose cell size. These high concentrations suggest that IL-6 might act as an autocrine/paracrine regulator in the adipose tissue. Adipose tissue biopsies were also incubated in vitro to examine the effects of IL-6. Several important adipose tissue differentiation markers such as adiponectin, aP2 and PPARgamma2 were decreased. Thus, high local IL-6 concentrations, as seen in obesity, can impair the differentiation of the adipose cells.In Paper II, we characterized the effects of PPARgamma and C/EBPalpha of adiponectin and aP2 expression. We differentiated C/EBPalpha-/- fibroblasts and found that PPARgamma2 was necessary for adiponectin expression but C/EBPalpha was required for full gene activation. We also found that the PPARgamma ligand, pioglitazone, increased adiponectin expression in the absence of C/EBPalpha suggesting that the adiponectin promoter contains functional PPRE elements. Both IL-6 and TNFalpha reduced the expression of the differentiation markers adiponectin and aP2. However, over-expressing C/EBPalpha prevented this effect of IL-6.In Paper III, we found that IL-6 impaired the terminal differentiation of preadipocytes to adipose cells and reduced the lipid accumulation. However, TNFalpha completely prevented differentiation. IL-6, like TNFalpha, reduced the expression of most genes related to normal adipocyte function, insulin signalling and action. Remarkably, the canonical Wnt signalling pathway remained activated in the presence of either IL-6 or TNFalpha. This was associated with low axin and high beta-catenin, thereby keeping the cells in a proliferative mode and preventing the terminal differentiation. Instead, both IL-6 and TNFalpha promoted an inflammatory phenotype of the (pre)adipocytes.CONCLUSIONS: Interstitial IL-6 levels in the adipose tissue were markedly higher than circulating IL-6 concentrations and correlated positively with adipose cell size. The inhibitory effect of IL-6 on adiponectin mRNA levels was prevented by over-expressing C/EBPalpha. Both IL-6 and TNFalpha impaired, or prevented, the normal preadipocyte differentiation to mature adipose cells and, instead, promoted an inflammatory phenotype. This was associated with a maintained Wnt signalling, thus preventing the normal differentiation. Together, these findings provide an explanation to why obesity is associated with insulin resistance, inflammation and ectopic lipid accumulation in other tissues.
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| 7. |
- Gustafson, Birgit, 1951, et al.
(author)
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Inflamed Adipose Tissue: A Culprit Underlying the Metabolic Syndrome and Atherosclerosis
- 2007
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In: Arterioscler Thromb Vasc Biol. - 1524-4636. ; 27
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Journal article (peer-reviewed)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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| 8. |
- Gustafson, Birgit, 1951, et al.
(author)
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Inflammation and impaired adipogenesis in hypertrophic obesity in man
- 2009
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In: Am J Physiol Endocrinol Metab. - 0193-1849. ; 297
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Journal article (peer-reviewed)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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| 9. |
- Gustafson, Birgit, 1951, et al.
(author)
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Insulin resistance and impaired adipogenesis
- 2015
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In: Trends in endocrinology and metabolism. - : Elsevier BV. - 1043-2760. ; 26:4, s. 193-200
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Research review (peer-reviewed)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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| 10. |
- Gustafson, Birgit, 1951, et al.
(author)
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Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells
- 2019
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Journal article (peer-reviewed)abstract
- Inappropriate expansion of the adipose cells in the subcutaneous adipose tissue (SAT) is a characteristic of hypertrophic obesity and of individuals with genetic predisposition for T2D (first-degree relatives; FDR). It is associated with insulin resistance, a dysfunctional, adipose tissue and reduced adipogenesis. We examined the regulation of adipogenesis in human SAT precursor cells and found ZNF521 to be a critical regulator of early adipogenic commitment and precursor cells leaving the cell cycle. However, neither altered upstream signalling nor lack of SAT progenitor cells could explain the reduced adipogenesis in hypertrophic obesity. Instead, we show that progenitor cells undergoing poor differentiation are characterized by senescence, inability to suppress p53/P16(INK4) and secretion of factors reducing adipogenesis in non-senescent cells. We found aging, FDR and established T2D to be associated with increased progenitor cell senescence, reduced adipogenesis and hypertrophic expansion of the SAT adipose cells.
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