Publications by authors named "Daniel Tews"

12 Publications

  • Page 1 of 1

Combined Cardioprotective and Adipocyte Browning Effects Promoted by the Eutomer of Dual sEH/PPARγ Modulator.

J Med Chem 2021 Feb 23. Epub 2021 Feb 23.

Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.

The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARγ agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARγ agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARγ modulator RB394 () simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of . We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARγ modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c02063DOI Listing
February 2021

Rosmarinic acid attenuates obesity and obesity-related inflammation in human adipocytes.

Food Chem Toxicol 2021 Mar 19;149:112002. Epub 2021 Jan 19.

Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, Plovdiv, Bulgaria; Laboratory of Metabolomics, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Plovdiv, Bulgaria. Electronic address:

Chronic low-grade inflammation is a hallmark of obesity and its related metabolic disorders. At the same time signaling from pro-inflammatory factors such as transforming growth factor beta (TGF-β) or interleukin 17A (IL-17A) are proposed as crucial for the commitment of fibroblast progenitor cells towards adipogenic differentiation. Modulation of inflammation during adipogenic differentiation is incompletely explored as a potential approach to prevent metabolic disorders. Rosmarinic acid (RA) is a caffeic acid derivative known for its anti-inflammatory effects. Experimental studies of its activity on adipogenic factors or in vivo obesity models are, however, controversial and hence insufficient. Here, we investigated the anti-adipogenic action of RA in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. Gene expression levels of key players in adipogenesis and lipid metabolism were assessed. Furthermore, a molecular mechanism of action was proposed. The most prominent effect was found on the translation of C/EBPα, PPARγ and adiponectin, as well as on the modulation of TGF1B and IL17A. Interestingly, involvement of NRF2 signaling was identified upon RA treatment. In summary, our findings indicate that RA prevents inflammation and excessive lipid accumulation in human adipocytes. Data from the molecular analysis demonstrate that RA has potential for treatment of obesity and obesity-related inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fct.2021.112002DOI Listing
March 2021

CD90 Is Dispensable for White and Beige/Brown Adipocyte Differentiation.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Division of Pediatric Endocrinology and Diabetes, Ulm University Medical Center, 89075 Ulm, Germany.

Brown adipose tissue (BAT) is a thermogenic organ in rodents and humans. In mice, the transplantation of BAT has been successfully used to combat obesity and its comorbidities. While such beneficial properties of BAT are now evident, the developmental and cellular origins of brown, beige, and white adipocytes have remained only poorly understood, especially in humans. We recently discovered that CD90 is highly expressed in stromal cells isolated from human white adipose tissue (WAT) compared to BAT. Here, we studied whether CD90 interferes with brown or white adipogenesis or white adipocyte beiging. We applied flow cytometric sorting of human adipose tissue stromal cells (ASCs), a CRISPR/Cas9 knockout strategy in the human Simpson-Golabi-Behmel syndrome (SGBS) adipocyte model system, as well as a siRNA approach in human approaches supports the hypothesis that CD90 affects brown or white adipogenesis or white adipocyte beiging in humans. Taken together, our findings call the conclusions drawn from previous studies, which claimed a central role of CD90 in adipocyte differentiation, into question.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21217907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663553PMC
October 2020

Age- and BMI-Associated Expression of Angiogenic Factors in White Adipose Tissue of Children.

Int J Mol Sci 2019 Oct 21;20(20). Epub 2019 Oct 21.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 89075 Ulm, Germany.

The growth of adipose tissue and its vasculature are tightly associated. Angiogenic factors have been linked to obesity, yet little is known about their expression during early childhood. To identify associations of angiogenic factors with characteristics on individual and tissue level, subcutaneous white adipose tissue samples were taken from 45 children aged 0-9 years undergoing elective surgery. We measured the expression of vascular endothelial growth factor A (VEFGA), fibroblast growth factor 1 and 2 (FGF1, FGF2), angiopoietin 1 and 2 (ANGPT1, ANGPT2), TEK receptor tyrosine kinase (TEK), and von Willebrand factor (VWF). In addition, we determined the mean adipocyte size in histologic tissue sections. We found positive correlations of age with FGF1 and FGF2 and a negative correlation with ANGPT2, with pronounced differences in the first two years of life. FGF1, FGF2, and ANGPT1 correlated positively with adipocyte size. Furthermore, we identified a correlation of ANGPT1 and TEK with body mass index-standard deviation score (BMI-SDS), a measure to define childhood obesity. Except for ANGPT2, all angiogenic factors correlated positively with the endothelial marker VWF. In sum, our findings suggest that differences related to BMI-SDS begin early in childhood, and the analyzed angiogenic factors possess distinct roles in adipose tissue biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20205204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829445PMC
October 2019

Activated macrophages control human adipocyte mitochondrial bioenergetics via secreted factors.

Mol Metab 2017 10 19;6(10):1226-1239. Epub 2017 Jul 19.

Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der LMU, 80336 München, Germany.

Objective: Obesity-associated WAT inflammation is characterized by the accumulation and local activation of macrophages (MΦs), and recent data from mouse studies suggest that macrophages are modifiers of adipocyte energy metabolism and mitochondrial function. As mitochondrial dysfunction has been associated with obesity and the metabolic syndrome in humans, herein we aimed to delineate how human macrophages may affect energy metabolism of white adipocytes.

Methods: Human adipose tissue gene expression analysis for markers of macrophage activation and tissue inflammation (CD11c, CD40, CD163, CD206, CD80, MCP1, TNFα) in relationship to mitochondrial complex I (NDUFB8) and complex III (UQCRC2) was performed on subcutaneous WAT of 24 women (BMI 20-61 kg/m). Guided by these results, the impact of secreted factors of LPS/IFNγ- and IL10/TGFβ-activated human macrophages (THP1, primary blood-derived) on mitochondrial function in human subcutaneous white adipocytes (SGBS, primary) was determined by extracellular flux analysis (Seahorse technology) and gene/protein expression.

Results: Stepwise regression analysis of human WAT gene expression data revealed that a linear combination of CD40 and CD163 was the strongest predictor for mitochondrial complex I (NDUFB8) and complex III (UQCRC2) levels, independent of BMI. IL10/TGFβ-activated MΦs displayed high CD163 and low CD40 expression and secreted factors that decreased UQCRC2 gene/protein expression and ATP-linked respiration in human white adipocytes. In contrast, LPS/IFNγ-activated MΦs showed high CD40 and low CD163 expression and secreted factors that enhanced adipocyte mitochondrial activity resulting in a total difference of 37% in ATP-linked respiration of white adipocytes (p = 0.0024) when comparing the effect of LPS/IFNγ- vs IL10/TGFβ-activated MΦs.

Conclusion: Our data demonstrate that macrophages modulate human adipocyte energy metabolism via an activation-dependent paracrine mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2017.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641636PMC
October 2017

miR-146a-mediated suppression of the inflammatory response in human adipocytes.

Sci Rep 2016 12 6;6:38339. Epub 2016 Dec 6.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatric and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

The obesity-associated inflammation of white adipose tissue (WAT) is one of the factors leading to the development of related diseases such as insulin resistance and liver steatosis. Recently, microRNAs (miRNAs) were identified as important regulators of WAT functions. Herein, we cultured human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes with macrophage-conditioned medium (MacCM) and performed an Affimetrix miRNA array to identify miRNAs differentially expressed under inflammatory conditions. We identified 24 miRNAs differentially expressed upon inflammation in human adipocytes and miR-146a was the most up-regulated miRNA species. In subcutaneous WAT, miR-146a was elevated in both human and murine obesity. Transfection of miR-146a mimics prevented the MacCM-induced inflammatory response in SGBS adipocytes as seen by reduced levels of IL-8 and MCP-1 mRNA and protein. We identified IRAK1 and TRAF6 as targets of miR-146a in human adipocytes and detected a reduced inflammation-induced activation of JNK and p38 upon miR-146a transfection. Taken together, we could show that miR-146a reduces the inflammatory response in human adipocytes. In a negative feedback loop miR-146a might contribute to the regulation of inflammatory processes in WAT and possibly prevent an overwhelming inflammatory response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep38339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138634PMC
December 2016

miR-125b affects mitochondrial biogenesis and impairs brite adipocyte formation and function.

Mol Metab 2016 Aug 15;5(8):615-625. Epub 2016 Jun 15.

Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France. Electronic address:

Objective: In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed "brite" (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or β3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation.

Methods/results: Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. In vitro, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. In vivo, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon β3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased β3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis.

Conclusion: Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2016.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021678PMC
August 2016

Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype.

J Transl Med 2015 Apr 30;13:135. Epub 2015 Apr 30.

Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, P.O. Box 24144, Doha, Qatar.

Background: Functional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target.

Methods And Results: Molecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARγ peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent with the molecular patterns. Accordingly, the oxidative capacity of SGBS adipocytes peaked on differentiation day 14 and declined progressively towards differentiation day 28.

Conclusions: Our studies have unveiled a new phenotype of human adipocytes, providing a tool to identify molecular gene expression patterns and pathways involved in the conversion between white and brown adipocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-015-0480-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438513PMC
April 2015

Absence of CC chemokine receptors 2a and 2b from human adipose lineage cells.

Mol Cell Endocrinol 2013 Apr 29;369(1-2):72-85. Epub 2013 Jan 29.

Institute of Pharmacology and Toxicology, Ulm University Medical Center, Ulm, Germany.

Previous results have suggested the existence of receptors for monocyte chemoattractant protein-1 (MCP-1), CC chemokine receptors 2 (CCR2), in human adipocytes and their involvement in mediating effects of MCP-1 on adipocyte functions. However, the presence of CCR2 present on non-adipose-lineage cells of adipose tissue has not been excluded. We have used human Simpson-Golabi-Behmel-Syndrome (SGBS) preadipocytes and in-vitro-differentiated mature adipocytes to investigate the expression of CCR2 in human (pre)adipocytes. We found that the cells are devoid of CCR2 receptor protein and mRNA expression and fail to respond to treatment with all known CCR2 chemokine agonists. CCR2 is also absent from (pre)adipocytes prepared in vitro from human multipotent adipose-derived stem cells, bone-marrow-derived mesenchymal stem cells, or from primary (pre)adipocytes. Conditions mimicking proinflammatory changes in adipose tissue did not induce CCR2 receptor expression. We conclude that CCR2 is absent from human adipose lineage cells. Functional effects previously described for MCP-1 in human adipose tissue may be mediated indirectly through paracrine effects on non-adipose-lineage cells or by a (pre)adipocyte receptor for MCP-1 distinct from CCR2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2013.01.008DOI Listing
April 2013

Differential function of Akt1 and Akt2 in human adipocytes.

Mol Cell Endocrinol 2012 Jul 29;358(1):135-43. Epub 2012 Mar 29.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Eythstr. 24, 89075 Ulm, Germany.

Adipose tissue mass is determined by both cell size and cell number. Mouse models suggest that Akt isoforms are involved in the determination of fat mass by interfering with preadipocyte-to-adipocyte transition and regulating lipid storage. Here, we took advantage of a lentiviral mediated shRNA approach to study the role of Akt1 and Akt2 in differentiation and metabolism of human SGBS adipocytes. Adipogenic differentiation as measured by lipid accumulation was robustly inhibited in Akt2 deficient cells, whereas it was not affected by knockdown of Akt1. The knockdown of Akt2 caused an almost complete inhibition of preadipocyte proliferation. Furthermore, Akt2 deficient preadipocytes were significantly more sensitive to apoptosis induction by death receptor stimulation compared to Akt1 deficient cells. Both the knockdown of Akt1 or Akt2 equally affected insulin-stimulated lipogenesis as well as the anti-lipolytic effect of insulin. We conclude that Akt2 is indispensable for the regulation of preadipocyte and adipocyte number, whereas Akt1 and Akt2 are equally important for the regulation of insulin-stimulated metabolic pathways in human adipocytes. Recently proposed as an attractive target for the treatment of cancer, modulating Akt2 activity might also be a new molecular strategy to control adipose tissue mass.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2012.03.018DOI Listing
July 2012

Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner.

Am J Clin Nutr 2010 Jul 12;92(1):5-15. Epub 2010 May 12.

Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany.

Background: Caloric restriction leads to retardation of the aging processes and to longer life in many organisms. This effect of caloric restriction can be mimicked by resveratrol, a natural plant product present in grapes and red wine, which is known as a potent activator of sirtuin 1 [silent mating type information regulation 2 homolog 1 (Sirt1)].

Objectives: One main effect of caloric restriction in mammals is a reduction of body fat from white adipose tissue. We sought to identify the effects of resveratrol on fat cell biology and to elucidate whether Sirt1 is involved in resveratrol-mediated changes.

Design: Human Simpson-Golabi-Behmel syndrome preadipocytes and adipocytes were used to study proliferation, adipogenic differentiation, glucose uptake, de novo lipogenesis, and adipokine secretion. Sirt1-deficient human preadipocytes were generated by using a lentiviral small hairpin RNA system to study the role of Sirt1 in resveratrol-mediated changes.

Results: Resveratrol inhibited preadipocyte proliferation and adipogenic differentiation in a Sirt1-dependent manner. In human adipocytes, resveratrol stimulated basal and insulin-stimulated glucose uptake. De novo lipogenesis was inhibited in parallel with a down-regulation of lipogenic gene expression. Furthermore, resveratrol down-regulated the expression and secretion of interleukin-6 and interleukin-8. Sirt1 was only partially responsible for the regulation of resveratrol-mediated changes in adipokine secretion.

Conclusions: Taken together, our data suggest that resveratrol influences adipose tissue mass and function in a way that may positively interfere with the development of obesity-related comorbidities. Thus, our findings open up the new perspective that resveratrol-induced intracellular pathways could be a target for prevention or treatment of obesity-associated endocrine and metabolic adverse effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3945/ajcn.2009.28435DOI Listing
July 2010

Skeletal muscle insulin resistance induced by adipocyte-conditioned medium: underlying mechanisms and reversibility.

Am J Physiol Endocrinol Metab 2008 Jun 25;294(6):E1070-7. Epub 2008 Mar 25.

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.

Insulin resistance in skeletal muscle is an early event in the development of diabetes, with obesity being one of the major contributing factors. In vitro, conditioned medium (CM) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells, but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process. CM induced insulin resistance in human myotubes at the level of insulin-stimulated Akt and GSK-3 phosphorylation. In addition, insulin-resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD. However, insulin resistance was not paralleled by increased apopotosis. Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling. However, the expression level of myogenin could not be reestablished. In addition to decreasing myogenin expression, CM also decreased the release of IL-6 and IL-8 and increased monocyte chemotactic protein-1 (MCP-1) secretion from skeletal muscle cells. Although regeneration of myotubes reestablished normal secretion of IL-6, the release of IL-8 and MCP-1 remained impaired for 48 h after withdrawal of CM. In conclusion, our data show that insulin resistance in skeletal muscle cells is only partially reversible. Although some characteristic features of insulin-resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM, others such as IL-8 and MCP-1 secretion and myogenin expression remain impaired over a longer period. Thus, we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpendo.00529.2007DOI Listing
June 2008