cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.19673526.v1
title: Adipose Tissue from Subjects with Type 2 Diabetes Exhibits Impaired Capillary Formation in Response to GROα: Involvement of MMPs-2 and -9

description: Type 2 Diabetes (T2D) is associated with impaired vascularization of adipose tissue (AT) and skeletal muscle. IL8, GROα and IL15 are pro-angiogenic myokines; T2D myotubes secrete high levels of all 3 factors. We aimed to explore the direct impact of these myokines on AT vascularization. Subcutaneous AT explants from subjects with T2D (n=15) and without diabetes (non-diabetic, ND, n=14) subjects were treated with rIL8, rGROα and rIL15 in concentrations equal to those in conditioned media (CM) from T2D and ND myotubes, and sprout formation evaluated. Endothelial cells (EC) were isolated from T2D and ND-AT, treated with rGROα and tube formation evaluated. Finally, we investigated the involvement of MMP-2 and -9 in AT vascularization. ND and T2D concentrations of IL8 or IL15 individually or as IL8 + IL15 + GROα caused similar stimulation of sprout formation in ND- and T2D-AT. GROα alone exerted a similar effect in ND-AT. However, when T2D-AT explants were exposed to GROα alone, sprout formation in response to T2D concentrations was reduced compared to ND (p&lt;0.05). Endothelial-cells (EC) isolated from T2D and ND-AT and treated with GROα exhibited a similar response to that of AT. Exposure of EC from T2D-AT to GROα at T2D concentrations resulted in reduced tube formation compared to ND-AT (p&lt;0.005). Reduced responses to GROα in T2D-AT and EC were also seen for secretion of MMP-2 and -9. The data indicate that skeletal muscle can potentially regulate AT vascularization, with T2D-AT having impairments in sensitivity to GROα and secretion of MMP-2 and -9, while responding normally to IL8 and IL15.
DOI: 10.6084/m9.figshare.21220597.v1
title: Dipeptidyl peptidase–4 cell surface expression marks an abundant adipose stem/progenitor cell population with high stemness in human white adipose tissue

description: The capacity of adipose stem/progenitor cells (ASC) to undergo self-renewal and differentiation is crucial for adipose tissue homeostasis, regeneration and expansion. However, the heterogeneous ASC populations of the adipose lineage constituting adipose tissue are not precisely known. In the present study, we demonstrate that cell surface expression of Dipeptidyl peptidase-4 (DPP4)/Cluster of differentiation 26 (CD26) subdivides the DLK1<sup>−</sup>/CD34<sup>+</sup>/CD45<sup>−</sup>/CD31<sup>−</sup> ASC pool of human white adipose tissues (WAT) into two large populations. Ex vivo, DPP4<sup>+</sup> ASC possess higher self-renewal and proliferation capacity and lesser adipocyte differentiation potential than DDP4<sup>−</sup> ASC. Knock down of DPP4 in ASC leads to significantly reduced proliferation and self-renewal capacity while adipogenic differentiation is increased. Ectopic overexpression of DPP4 strongly inhibits adipogenesis. Moreover, in whole mount stainings of human subcutaneous (s)WAT we detect DPP4 in CD34<sup>+</sup> ASC located in the vascular stroma surrounding small blood vessels and in mature adipocytes. We conclude that DPP4 is a functional marker for an abundant ASC population in human WAT with high proliferation and self-renewal potential and low adipogenic differentiation capacity.
DOI: 10.6084/m9.figshare.19611736
title: Contribution of markers of adiposopathy and adipose cell size in predicting insulin resistance in women of varying age and adiposity

description: Adipose tissue (AT) dysfunctions, such as adipocyte hypertrophy, macrophage infiltration and secretory adiposopathy (low plasma adiponectin/leptin, A/L, ratio), associate with metabolic disorders. However, no study has compared the relative contribution of these markers to cardiometabolic risk in women of varying age and adiposity. Body composition, regional AT distribution, lipid-lipoprotein profile, glucose homeostasis and plasma A and L levels were determined in 67 women (age: 40-62 years; BMI: 17-41 kg/m<sup>2</sup>). Expression of macrophage infiltration marker CD68 and adipocyte size were measured from subcutaneous abdominal (SCABD) and omental (OME) fat. AT dysfunction markers correlated with most lipid-lipoprotein levels. The A/L ratio was negatively associated with fasting insulinemia and HOMA-IR, while SCABD or OME adipocyte size and SCABD CD68 expression were positively related to these variables. Combination of tertiles of largest adipocyte size and lowest A/L ratio showed the highest HOMA-IR. Multiple regression analyses including these markers and TAG levels revealed that the A/L ratio was the only predictor of fasting insulinemia and HOMA-IR. The contribution of the A/L ratio was superseded by adipose cell size in the model where the latter replaced TAGs. Finally, leptinemia was a better predictor of IR than adipocyte size and the A/L ratio in our participants sample.
DOI: 10.6084/m9.figshare.20131424.v1
title: Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity

description: High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.
DOI: 10.6084/m9.figshare.19375244
title: An organoid model derived from human adipose stem/progenitor cells to study adipose tissue physiology

description: We established a functional adipose organoid model system for human adipose stem/progenitor cells (ASCs) isolated from white adipose tissue (WAT). ASCs were forced to self-aggregate by a hanging-drop technique. Afterwards, spheroids were transferred into agar-coated cell culture dishes to avoid plastic-adherence and dis-aggregation. Adipocyte differentiation was induced by an adipogenic hormone cocktail. Morphometric analysis revealed a significant increase in organoid size in the course of adipogenesis until d 18. Whole mount staining of organoids using specific lipophilic dyes showed large multi- and unilocular fat deposits in differentiated cells indicating highly efficient differentiation of ASCs into mature adipocytes. Moreover, we found a strong induction of the expression of key adipogenesis and adipocyte markers (CCAAT/enhancer-binding protein (C/EBP) β, peroxisome proliferator-activated receptor (PPAR) γ, fatty acid-binding protein 4 (FABP4), adiponectin) during adipose organoid formation. Secreted adiponectin was detected in the cell culture supernatant, underscoring the physiological relevance of mature adipocytes in the organoid model. Moreover, colony formation assays of collagenase-digested organoids revealed the maintenance of a significant fraction of ASCs within newly formed organoids. In conclusion, we provide a reliable and highly efficient WAT organoid model, which enables accurate analysis of cellular and molecular markers of adipogenic differentiation and adipocyte physiology.
DOI: 10.6084/m9.figshare.19611736.v1
title: Contribution of markers of adiposopathy and adipose cell size in predicting insulin resistance in women of varying age and adiposity

description: Adipose tissue (AT) dysfunctions, such as adipocyte hypertrophy, macrophage infiltration and secretory adiposopathy (low plasma adiponectin/leptin, A/L, ratio), associate with metabolic disorders. However, no study has compared the relative contribution of these markers to cardiometabolic risk in women of varying age and adiposity. Body composition, regional AT distribution, lipid-lipoprotein profile, glucose homeostasis and plasma A and L levels were determined in 67 women (age: 40-62 years; BMI: 17-41 kg/m<sup>2</sup>). Expression of macrophage infiltration marker CD68 and adipocyte size were measured from subcutaneous abdominal (SCABD) and omental (OME) fat. AT dysfunction markers correlated with most lipid-lipoprotein levels. The A/L ratio was negatively associated with fasting insulinemia and HOMA-IR, while SCABD or OME adipocyte size and SCABD CD68 expression were positively related to these variables. Combination of tertiles of largest adipocyte size and lowest A/L ratio showed the highest HOMA-IR. Multiple regression analyses including these markers and TAG levels revealed that the A/L ratio was the only predictor of fasting insulinemia and HOMA-IR. The contribution of the A/L ratio was superseded by adipose cell size in the model where the latter replaced TAGs. Finally, leptinemia was a better predictor of IR than adipocyte size and the A/L ratio in our participants sample.
DOI: 10.6084/m9.figshare.20131424
title: Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity

description: High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.
DOI: 10.6084/m9.figshare.19375244.v1
title: An organoid model derived from human adipose stem/progenitor cells to study adipose tissue physiology

description: We established a functional adipose organoid model system for human adipose stem/progenitor cells (ASCs) isolated from white adipose tissue (WAT). ASCs were forced to self-aggregate by a hanging-drop technique. Afterwards, spheroids were transferred into agar-coated cell culture dishes to avoid plastic-adherence and dis-aggregation. Adipocyte differentiation was induced by an adipogenic hormone cocktail. Morphometric analysis revealed a significant increase in organoid size in the course of adipogenesis until d 18. Whole mount staining of organoids using specific lipophilic dyes showed large multi- and unilocular fat deposits in differentiated cells indicating highly efficient differentiation of ASCs into mature adipocytes. Moreover, we found a strong induction of the expression of key adipogenesis and adipocyte markers (CCAAT/enhancer-binding protein (C/EBP) β, peroxisome proliferator-activated receptor (PPAR) γ, fatty acid-binding protein 4 (FABP4), adiponectin) during adipose organoid formation. Secreted adiponectin was detected in the cell culture supernatant, underscoring the physiological relevance of mature adipocytes in the organoid model. Moreover, colony formation assays of collagenase-digested organoids revealed the maintenance of a significant fraction of ASCs within newly formed organoids. In conclusion, we provide a reliable and highly efficient WAT organoid model, which enables accurate analysis of cellular and molecular markers of adipogenic differentiation and adipocyte physiology.
DOI: 10.6084/m9.figshare.20502703
title: The effect of trimethylamine N-oxide on the metabolism of visceral white adipose tissue in spontaneously hypertensive rat

description: Strong links have been reported among trimethylamine N-oxide (TMAO), visceral white adipose tissue (vWAT), and cardiometabolic diseases. However, the effects of TMAO on vWAT in hypertension remained incompletely explored. The impact of a chronic 22-week-long treatment with 1 g/L TMAO on vWAT, and its transcriptional and metabolic changes in spontaneously hypertensive rats (SHRs) were evaluated by serum cytokine measurements, histological analysis, fatty acid determinations, and co-expression network analyses. TMAO increased the serum interleukin-6 levels and insulin secretion in SHRs. The adipocyte size was diminished in the SHR 1 g/L TMAO group. In addition, one kind of monounsaturated fatty acids (cis-15-tetracosenoate) and four kinds of polyunsaturated fatty acids (cis-11,14,17-eicosatrienoic acid, docosatetraenoate, docosapentaenoate n-3, and docosapentaenoate n-6) were elevated by TMAO treatment. Three co-expression modules significantly related to TMAO treatment were identified and pathway enrichment analyses indicated that phagosome, lysosome, fatty acid metabolism, valine, leucine, and isoleucine degradation and metabolic pathways were the most significantly altered biological pathways. This study shed new light on the metabolic roles of TMAO on the vWAT of SHRs. TMAO regulated the metabolic status of vWAT, including reduced lipogenesis and an improved specific fatty acid composition. The mechanisms underlying these effects likely involve phagosome and lysosome pathways.
DOI: 10.6084/m9.figshare.20502703.v1
title: The effect of trimethylamine N-oxide on the metabolism of visceral white adipose tissue in spontaneously hypertensive rat

description: Strong links have been reported among trimethylamine N-oxide (TMAO), visceral white adipose tissue (vWAT), and cardiometabolic diseases. However, the effects of TMAO on vWAT in hypertension remained incompletely explored. The impact of a chronic 22-week-long treatment with 1 g/L TMAO on vWAT, and its transcriptional and metabolic changes in spontaneously hypertensive rats (SHRs) were evaluated by serum cytokine measurements, histological analysis, fatty acid determinations, and co-expression network analyses. TMAO increased the serum interleukin-6 levels and insulin secretion in SHRs. The adipocyte size was diminished in the SHR 1 g/L TMAO group. In addition, one kind of monounsaturated fatty acids (cis-15-tetracosenoate) and four kinds of polyunsaturated fatty acids (cis-11,14,17-eicosatrienoic acid, docosatetraenoate, docosapentaenoate n-3, and docosapentaenoate n-6) were elevated by TMAO treatment. Three co-expression modules significantly related to TMAO treatment were identified and pathway enrichment analyses indicated that phagosome, lysosome, fatty acid metabolism, valine, leucine, and isoleucine degradation and metabolic pathways were the most significantly altered biological pathways. This study shed new light on the metabolic roles of TMAO on the vWAT of SHRs. TMAO regulated the metabolic status of vWAT, including reduced lipogenesis and an improved specific fatty acid composition. The mechanisms underlying these effects likely involve phagosome and lysosome pathways.
DOI: 10.6084/m9.figshare.20462565
title: Insulin prevents fatty acid induced increase of adipocyte size

description: Metabolic disorders related to obesity are largely dependent on adipose tissue hypertrophy, which involves adipocyte hypertrophy and increased adipogenesis. Adiposize is regulated by lipid accumulation as a result of increased lipogenesis (mainly lipid uptake in mature adipocytes) and reduced lipolysis. Using realtime 2D cell culture analyses of lipid uptake, we show (1) that high glucose concentration (4.5 g/L) was required to accumulate oleic acid increasing lipid droplet size until unilocularization similar to mature adipocytes in few days, (2) oleic acid reduced <i>Peroxisome-Proliferator Activated Receptor Gamma</i> (<i>PPARG)</i> gene transcription and (3) insulin counteracted oleic acid-induced increase of lipid droplet size. Although the lipolytic activity observed in high <i>versus</i> low glucose (1 g/L) conditions was not altered, insulin was found to inhibit oleic acid induced gene transcription required for lipid storage such as Cell Death Inducing DFFA Like Effectors (CIDEC) and <i>G0S2 (</i>G0 switch gene S2), possibly through PPARA activity. Although this signalling pathway requires more detailed investigation, the results point out the differential mechanisms involved in the pro-adipogenic effect of insulin in absence <i>versus</i> its protective effect on adiposity in presence of oleic acid uptake. <b>Abbreviations</b>: AICAR, 5-Aminoimidazole-4-carboxamide-1-D-ribofuranoside; AMPK, AMP-Activated protein kinase, ASCs, adipose stem cell; ATGL, adipose triglyceride lipase; BSA, Bovine serum albumin; CEBPA, CCAAT enhancer binding protein alpha; CIDEs, Cell Death Inducing DFFA Like Effectors; dA, differentiated adipocyte; DMEM, Dulbecco’s Modified Eagle’s Medium; FABPs, Fatty Acid Binding Proteins; FAT/CD36, Fatty acid translocase; FCS, Foetal calf serum; FN1, fibronectin 1; FFA, free fatty acid; G0S2, G0 switch gene S2; GLUTs, Glucose transporters; GPR120, G protein-coupled receptor 120; HG, high glucose; HSL, hormone sensitive lipase; INSR, insulin receptor; LG, low glucose; OA, oleic acid; PBS, Phosphate buffer saline; PPARs, Peroxisome-Proliferator Activated Receptors; PKA, Protein kinase cyclic AMP-dependent; PKG, Protein kinase cyclic GMP dependent; PTGS2, cytochrome oxidase 2; RTCA, realtime cell analysis; TG, triglyceride.
DOI: 10.6084/m9.figshare.20462565.v4
title: Insulin prevents fatty acid induced increase of adipocyte size

description: Metabolic disorders related to obesity are largely dependent on adipose tissue hypertrophy, which involves adipocyte hypertrophy and increased adipogenesis. Adiposize is regulated by lipid accumulation as a result of increased lipogenesis (mainly lipid uptake in mature adipocytes) and reduced lipolysis. Using realtime 2D cell culture analyses of lipid uptake, we show (1) that high glucose concentration (4.5 g/L) was required to accumulate oleic acid increasing lipid droplet size until unilocularization similar to mature adipocytes in few days, (2) oleic acid reduced <i>Peroxisome-Proliferator Activated Receptor Gamma</i> (<i>PPARG)</i> gene transcription and (3) insulin counteracted oleic acid-induced increase of lipid droplet size. Although the lipolytic activity observed in high <i>versus</i> low glucose (1 g/L) conditions was not altered, insulin was found to inhibit oleic acid induced gene transcription required for lipid storage such as Cell Death Inducing DFFA Like Effectors (CIDEC) and <i>G0S2 (</i>G0 switch gene S2), possibly through PPARA activity. Although this signalling pathway requires more detailed investigation, the results point out the differential mechanisms involved in the pro-adipogenic effect of insulin in absence <i>versus</i> its protective effect on adiposity in presence of oleic acid uptake. <b>Abbreviations</b>: AICAR, 5-Aminoimidazole-4-carboxamide-1-D-ribofuranoside; AMPK, AMP-Activated protein kinase, ASCs, adipose stem cell; ATGL, adipose triglyceride lipase; BSA, Bovine serum albumin; CEBPA, CCAAT enhancer binding protein alpha; CIDEs, Cell Death Inducing DFFA Like Effectors; dA, differentiated adipocyte; DMEM, Dulbecco’s Modified Eagle’s Medium; FABPs, Fatty Acid Binding Proteins; FAT/CD36, Fatty acid translocase; FCS, Foetal calf serum; FN1, fibronectin 1; FFA, free fatty acid; G0S2, G0 switch gene S2; GLUTs, Glucose transporters; GPR120, G protein-coupled receptor 120; HG, high glucose; HSL, hormone sensitive lipase; INSR, insulin receptor; LG, low glucose; OA, oleic acid; PBS, Phosphate buffer saline; PPARs, Peroxisome-Proliferator Activated Receptors; PKA, Protein kinase cyclic AMP-dependent; PKG, Protein kinase cyclic GMP dependent; PTGS2, cytochrome oxidase 2; RTCA, realtime cell analysis; TG, triglyceride.
DOI: 10.6084/m9.figshare.20462565.v3
title: Insulin prevents fatty acid induced increase of adipocyte size

description: Metabolic disorders related to obesity are largely dependent on adipose tissue hypertrophy, which involves adipocyte hypertrophy and increased adipogenesis. Adiposize is regulated by lipid accumulation as a result of increased lipogenesis (mainly lipid uptake in mature adipocytes) and reduced lipolysis. Using realtime 2D cell culture analyses of lipid uptake, we show (1) that high glucose concentration (4.5 g/L) was required to accumulate oleic acid increasing lipid droplet size until unilocularization similar to mature adipocytes in few days, (2) oleic acid reduced <i>Peroxisome-Proliferator Activated Receptor Gamma</i> (<i>PPARG)</i> gene transcription and (3) insulin counteracted oleic acid-induced increase of lipid droplet size. Although the lipolytic activity observed in high <i>versus</i> low glucose (1 g/L) conditions was not altered, insulin was found to inhibit oleic acid induced gene transcription required for lipid storage such as Cell Death Inducing DFFA Like Effectors (CIDEC) and <i>G0S2 (</i>G0 switch gene S2), possibly through PPARA activity. Although this signalling pathway requires more detailed investigation, the results point out the differential mechanisms involved in the pro-adipogenic effect of insulin in absence <i>versus</i> its protective effect on adiposity in presence of oleic acid uptake. <b>Abbreviations</b>: AICAR, 5-Aminoimidazole-4-carboxamide-1-D-ribofuranoside; AMPK, AMP-Activated protein kinase, ASCs, adipose stem cell; ATGL, adipose triglyceride lipase; BSA, Bovine serum albumin; CEBPA, CCAAT enhancer binding protein alpha; CIDEs, Cell Death Inducing DFFA Like Effectors; dA, differentiated adipocyte; DMEM, Dulbecco’s Modified Eagle’s Medium; FABPs, Fatty Acid Binding Proteins; FAT/CD36, Fatty acid translocase; FCS, Foetal calf serum; FN1, fibronectin 1; FFA, free fatty acid; G0S2, G0 switch gene S2; GLUTs, Glucose transporters; GPR120, G protein-coupled receptor 120; HG, high glucose; HSL, hormone sensitive lipase; INSR, insulin receptor; LG, low glucose; OA, oleic acid; PBS, Phosphate buffer saline; PPARs, Peroxisome-Proliferator Activated Receptors; PKA, Protein kinase cyclic AMP-dependent; PKG, Protein kinase cyclic GMP dependent; PTGS2, cytochrome oxidase 2; RTCA, realtime cell analysis; TG, triglyceride.