| 1. |
- McCulloch, Laura J, et al.
(författare)
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COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity.
- 2015
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:1, s. 134-46
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Tidskriftsartikel (refereegranskat)abstract
- Fibrosis of adipose tissue (AT) increases AT rigidity, reduces its expandability and contributes to metabolic dysfunction. Collagen type VI, alpha3 (COL6A3) encodes one subunit of a fibrotic extracellular matrix (ECM) protein highly expressed in rodent AT. Knock-out of collagen VI in rodent AT led to a significant improvement in metabolic health in obese, diabetic (ob/ob) mice however, it is unknown whether this collagen has the same metabolic significance in human AT. We therefore aimed to undertake a comprehensive assessment of COL6A3 in relation to human AT and obesity. Characterisation of COL6A3 in human AT showed 5 fold higher expression in the stromalvascular fraction compared with adipocyte expression and significantly higher expression in subcutaneous than omental AT. In both depots COL6A3 expression appeared to be lowered in obesity, whilst diet and surgery-induced weight loss increased COL6A3 expression in subcutaneous AT. Leptin treatment caused a dose dependent decrease in COL6A3 expression although no effect was seen with insulin or glucose treatment and no difference observed in subjects with diabetes. In addition, we found that the collagen expression profile in humans differs significantly from rodents as COL6A3 does not appear to be the predominant collagen in adipose, muscle or liver. Our findings oppose those initially seen in rodent studies and most importantly, demonstrate a direct regulation of COL6A3 by leptin. This highlights the importance of a paracrine leptin signalling pathway in human AT and suggests an additional mechanism by which leptin can regulate ECM composition and with it AT expandability.
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| 2. |
- Claussnitzer, Melina, et al.
(författare)
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Leveraging cross-species transcription factor binding site patterns: from diabetes risk Loci to disease mechanisms.
- 2014
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 156:1-2, s. 343-358
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
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| 3. |
- Doncheva, Atanaska, I, et al.
(författare)
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Serglycin Is Involved in Adipose Tissue Inflammation in Obesity
- 2022
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 208:1, s. 121-132
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Tidskriftsartikel (refereegranskat)abstract
- Chronic local inflammation of adipose tissue is an important feature of obesity. Serglycin is a proteoglycan highly expressed by various immune cell types known to infiltrate adipose tissue under obese conditions. To investigate if serglycin expression has an impact on diet-induced adipose tissue inflammation, we subjected Srgn(+/+) and Srgn(-/-) mice (C57BL/6J genetic background) to an 8-wk high-fat and high-sucrose diet. The total body weight was the same in Srgn(+/+) and Srgn(-/-) mice after diet treatment. Expression of white adipose tissue genes linked to inflammatory pathways were lower in Srgn(-/)- mice. We also noted reduced total macrophage abundance, a reduced proportion of proinflammatory M1 macrophages, and reduced formation of crown-like structures in adipose tissue of Srgn(-/-) compared with Srgn(+/+) mice. Further, Srgn(-/-) mice had more medium-sized adipocytes and fewer large adipocytes. Differentiation of preadipocytes into adipocytes (3T3-L1) was accompanied by reduced Srgn mRNA expression. In line with this, analysis of single-cell RNA sequencing data from mouse and human adipose tissue supports that Srgn mRNA is predominantly expressed by various immune cells, with low expression in adipocytes. Srgn mRNA expression was higher in obese compared with lean humans and mice, accompanied by an increased expression of immune cell gene markers. SRGN and inflammatory marker mRNA expression was reduced upon substantial weight loss in patients after bariatric surgery. Taken together, this study introduces a role for serglycin in the regulation of obesity-induced adipose inflammation.
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| 4. |
- Meen, Astri J., et al.
(författare)
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Obesity Is Associated with Distorted Proteoglycan Expression in Adipose Tissue
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:8
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Tidskriftsartikel (refereegranskat)abstract
- Proteoglycans are central components of the extracellular matrix (ECM) and binding partners for inflammatory chemokines. Morphological differences in the ECM and increased inflammation are prominent features of the white adipose tissues in patients with obesity. The impact of obesity and weight loss on the expression of specific proteoglycans in adipose tissue is not well known. This study aimed to investigate the relationship between adiposity and proteoglycan expression. We analyzed transcriptomic data from two human bariatric surgery cohorts. In addition, RT-qPCR was performed on adipose tissues from female and male mice fed a high-fat diet. Both visceral and subcutaneous adipose tissue depots were analyzed. Adipose mRNA expression of specific proteoglycans, proteoglycan biosynthetic enzymes, proteoglycan partner molecules, and other ECM-related proteins were altered in both human cohorts. We consistently observed more profound alterations in gene expression of ECM targets in the visceral adipose tissues after surgery (among others VCAN (p = 0.000309), OGN (p = 0.000976), GPC4 (p = 0.00525), COL1A1 (p = 0.00221)). Further, gene analyses in mice revealed sex differences in these two tissue compartments in obese mice. We suggest that adipose tissue repair is still in progress long after surgery, which may reflect challenges in remodeling increased adipose tissues. This study can provide the basis for more mechanistic studies on the role of proteoglycans in adipose tissues in obesity.
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