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1. Expression of Intelectin-1, also known as Omentin-1, is related to clinical phenotypes such as overweight, obesity, insulin resistance, and changes after bariatric surgery

Author

Paul Czechowski, Tobias Hagemann, Adhideb Ghosh, Wenfei Sun, Hua Dong, Falko Noé, Corinna Niersmann, Isabel Reinisch, Christian Wolfrum, Christian Herder, Arne Dietrich, Matthias Blüher, and Anne Hoffmann

Subjects
Medicine, Science
Abstract

Abstract Intelectin-1 (ITLN1; also Omentin-1, OMNT1) is secreted by adipose tissue (AT) and plays an important role in glucose metabolism regulation, with links to obesity-associated diseases. ITLN1 activity so far has rarely been investigated using RNA-sequencing and in larger cohorts. We evaluated ITLN1 expression among three clinical cohorts of the Leipzig Obesity BioBank—a cross-sectional cohort comprising of 1480 people, a cohort of people with metabolically healthy or unhealthy obesity (31 insulin-sensitive, 42 insulin-resistant individuals with obesity), and a longitudinal two-step bariatric surgery cohort (n = 65). We hypothesized that AT ITLN1 expression is associated with serum omentin-1, clinical parameters associated with obesity, and with weight loss after bariatric surgery. We also investigated the correlation of AT ITLN1 expression with genes related to inflammatory response, lipid metabolism, obesity, and regulation of energy balance. Likewise, we inspected gene group expression and metabolic pathways associated with ITLN1 expression using gene set enrichment and gene correlation analysis. We show that ITLN1 expression differs in VAT and SAT, and should therefore be analyzed separately. Furthermore, ITLN1 expression increases with VAT tissue mass, but is negatively affected by AT tissue dysfunction among individuals with unhealthy obesity, corroborated by interplay with genes related to tissue inflammation. Gene set enrichment and gene correlation analysis of ITLN1 expression suggest that AT ITLN1 expression is related to local inflammatory processes in AT, but also in processes such as regulation of appetite, energy balance, and maintenance of body weight.

Published
2024
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2. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Author

Rongling Wang, Mario Gomez Salazar, Iris Pruñonosa Cervera, Amanda Coutts, Karen French, Marlene Magalhaes Pinto, Sabrina Gohlke, Ruben García-Martín, Matthias Blüher, Christopher J. Schofield, Ioannis Kourtzelis, Roland H. Stimson, Cécile Bénézech, Mark Christian, Tim J. Schulz, Elias F. Gudmundsson, Lori L. Jennings, Vilmundur G. Gudnason, Triantafyllos Chavakis, Nicholas M. Morton, Valur Emilsson, and Zoi Michailidou

Subjects
Science
Abstract

Abstract Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)−2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.

Published
2024
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3. ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx

Author

Jonathan M. Dreyfuss, Vera Djordjilović, Hui Pan, Valerie Bussberg, Allison M. MacDonald, Niven R. Narain, Michael A. Kiebish, Matthias Blüher, Yu-Hua Tseng, and Matthew D. Lynes

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids’ association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

Published
2024
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4. Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape

Author

Isabel Reinisch, Helene Michenthaler, Alba Sulaj, Elisabeth Moyschewitz, Jelena Krstic, Markus Galhuber, Ruonan Xu, Zina Riahi, Tongtong Wang, Nemanja Vujic, Melina Amor, Riccardo Zenezini Chiozzi, Martin Wabitsch, Dagmar Kolb, Anastasia Georgiadi, Lisa Glawitsch, Ellen Heitzer, Tim J. Schulz, Michael Schupp, Wenfei Sun, Hua Dong, Adhideb Ghosh, Anne Hoffmann, Dagmar Kratky, Laura C. Hinte, Ferdinand von Meyenn, Albert J. R. Heck, Matthias Blüher, Stephan Herzig, Christian Wolfrum, and Andreas Prokesch

Subjects
Science
Abstract

Abstract In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.

Published
2024
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5. The application of high-performance ultrasound probes increases anatomic depiction in obese patients

Author

Sascha Heinitz, Jürgen Müller, Klaus-Vitold Jenderka, Haiko Schlögl, Michael Stumvoll, Matthias Blüher, Valentin Blank, and Thomas Karlas

Subjects
Medicine, Science
Abstract

Abstract This study evaluated the impact of obesity on abdominal ultrasound diagnostics and assessed effect of high-performance ultrasound probes increased imaging quality. Lean and obese subjects (n = 40; 58% female) were categorized according to body mass index (BMI, 21 to 48 kg/m2). A highly standardized ultrasound examination of the abdomen was performed by trained examiners using three different probes in randomized order (standard probe versus two high-performance probes). Quality of B-mode and duplex ultrasound were assessed using a custom scoring approach for depiction of liver and kidney anatomy and vascularization. Across probes, imaging quality of hepatic and kidney anatomy was inversely related with BMI (P < 0.03, r < − 0.35). Age, sex, and BMI explained 51% of the variance within the ultrasound quality score, with β = − 0.35, P < 0.0001 for BMI. Compared to the standard probe, high-performance probes allowed for a better depiction of kidney and liver anatomy in subjects above BMI 35 kg/m2 (n = 20, all P < 0.05), resulting in a less pronounced deterioration of imaging quality with increased BMI (all P < 0.05). In conclusion the study shows that obesity impairs ultrasound imaging quality of abdominal anatomy. The application of high-performance probes can increase anatomic depiction in obese patients. Registration number of the German Registry of Clinical Studies: DRKS00023498.

Published
2023
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6. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

Author

Petros Andrikopoulos, Judith Aron-Wisnewsky, Rima Chakaroun, Antonis Myridakis, Sofia K. Forslund, Trine Nielsen, Solia Adriouch, Bridget Holmes, Julien Chilloux, Sara Vieira-Silva, Gwen Falony, Joe-Elie Salem, Fabrizio Andreelli, Eugeni Belda, Julius Kieswich, Kanta Chechi, Francesc Puig-Castellvi, Mickael Chevalier, Emmanuelle Le Chatelier, Michael T. Olanipekun, Lesley Hoyles, Renato Alves, Gerard Helft, Richard Isnard, Lars Køber, Luis Pedro Coelho, Christine Rouault, Dominique Gauguier, Jens Peter Gøtze, Edi Prifti, Philippe Froguel, The MetaCardis Consortium, Jean-Daniel Zucker, Fredrik Bäckhed, Henrik Vestergaard, Torben Hansen, Jean-Michel Oppert, Matthias Blüher, Jens Nielsen, Jeroen Raes, Peer Bork, Muhammad M. Yaqoob, Michael Stumvoll, Oluf Pedersen, S. Dusko Ehrlich, Karine Clément, and Marc-Emmanuel Dumas

Subjects
Science
Abstract

Abstract The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied “explainable” machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.

Published
2023
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7. Delta weight loss unlike genetic variation associates with hyperoxaluria after malabsorptive bariatric surgery

Author

Lotte Scherer, Ria Schönauer, Melanie Nemitz-Kliemchen, Tobias Hagemann, Elena Hantmann, Jonathan de Fallois, Friederike Petzold, Matthias Blüher, and Jan Halbritter

Subjects
Medicine, Science
Abstract

Abstract The risk of enteric hyperoxaluria is significantly increased after malabsorptive bariatric surgery (MBS). However, its underlying determinants are only poorly characterized. In this case–control study, we aimed at identifying clinical and genetic factors to dissect their individual contributions to the development of post-surgical hyperoxaluria. We determined the prevalence of hyperoxaluria and nephrolithiasis after MBS by 24-h urine samples and clinical questionnaires at our obesity center. Both hyperoxaluric and non-hyperoxaluric patients were screened for sequence variations in known and candidate genes implicated in hyperoxaluria (AGXT, GRHPR, HOGA1, SLC26A1, SLC26A6, SLC26A7) by targeted next generation sequencing (tNGS). The cohort comprised 67 patients, 49 females (73%) and 18 males (27%). While hyperoxaluria was found in 29 patients (43%), only one patient reported postprocedural nephrolithiasis within 41 months of follow-up. Upon tNGS, we did not find a difference regarding the burden of (rare) variants between hyperoxaluric and non-hyperoxaluric patients. However, patients with hyperoxaluria showed significantly greater weight loss accompanied by markers of intestinal malabsorption compared to non-hyperoxaluric controls. While enteric hyperoxaluria is very common after MBS, genetic variation of known hyperoxaluria genes contributes little to its pathogenesis. In contrast, the degree of postsurgical weight loss and levels of malabsorption parameters may allow for predicting the risk of enteric hyperoxaluria and consecutive kidney stone formation.

Published
2023
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8. Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

Author

Giorgio Caratti, Ulrich Stifel, Bozhena Caratti, Ali J. M. Jamil, Kyoung-Jin Chung, Michael Kiehntopf, Markus H. Gräler, Matthias Blüher, Alexander Rauch, and Jan P. Tuckermann

Subjects
Science
Abstract

Abstract Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis. In contrast, GR deletion in Kupffer cells alone does not alter IR. Co-culture experiments show that the absence of GR in macrophages directly causes reduced phospho-AKT and glucose uptake in adipocytes, suggesting an important function of GR in ATM. GR-deficient macrophages are refractory to alternative ATM-inducing IL-4 signaling, due to reduced STAT6 chromatin loading and diminished anti-inflammatory enhancer activation. We demonstrate that GR has an important function in macrophages during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity.

Published
2023
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9. An integrated single cell and spatial transcriptomic map of human white adipose tissue

Author

Lucas Massier, Jutta Jalkanen, Merve Elmastas, Jiawei Zhong, Tongtong Wang, Pamela A. Nono Nankam, Scott Frendo-Cumbo, Jesper Bäckdahl, Narmadha Subramanian, Takuya Sekine, Alastair G. Kerr, Ben T. P. Tseng, Jurga Laurencikiene, Marcus Buggert, Magda Lourda, Karolina Kublickiene, Nayanika Bhalla, Alma Andersson, Armand Valsesia, Arne Astrup, Ellen E. Blaak, Patrik L. Ståhl, Nathalie Viguerie, Dominique Langin, Christian Wolfrum, Matthias Blüher, Mikael Rydén, and Niklas Mejhert

Subjects
Science
Abstract

Single-cell studies of human white adipose tissue (WAT) provide insights into the specialized cell types in the tissue. Here the authors combine publicly available and newly generated high-resolution and bulk transcriptomic results from multiple human datasets to provide a comprehensive cellular map of white adipose tissue.

Published
2023
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10. Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice

Author

Xuanchun Wang, Yanliang Li, Guifen Qiang, Kaihua Wang, Jiarong Dai, Maximilian McCann, Marcos D. Munoz, Victoria Gil, Yifei Yu, Shengxian Li, Zhihong Yang, Shanshan Xu, Jose Cordoba-Chacon, Dario F. De Jesus, Bei Sun, Kuangyang Chen, Yahao Wang, Xiaoxia Liu, Qing Miao, Linuo Zhou, Renming Hu, Qiang Ding, Rohit N. Kulkarni, Daming Gao, Matthias Blüher, and Chong Wee Liew

Subjects
Science
Abstract

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a secreted protein of incompletely understood physiological function. Here the authors show that scEMC10 is upregulated in people with obesity, and that that genetic EMC10 deletion or antibody-based neutralization of EMC10 prevents diet-induced obesity in mice.

Published
2022
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11. Analytical and computational workflow for in-depth analysis of oxidized complex lipids in blood plasma

Author

Angela Criscuolo, Palina Nepachalovich, Diego Fernando Garcia-del Rio, Mike Lange, Zhixu Ni, Massimo Baroni, Gabriele Cruciani, Laura Goracci, Matthias Blüher, and Maria Fedorova

Subjects
Science
Abstract

Oxidized lipids are prominent bioactive agents, and yet their molecular repertoire remains largely unknown. Here, the authors apply bioinformatics and LC-MS/MS to uncover the diversity and specificity of modified lipids in human blood plasma of lean and obese individuals.

Published
2022
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12. Adipose expression of CREB3L3 modulates body weight during obesity

Author

Maximilian A. McCann, Yanliang Li, Marcos Muñoz, Victoria Gil, Guifen Qiang, Jose Cordoba-Chacon, Matthias Blüher, Stephen Duncan, and Chong Wee Liew

Subjects
Medicine, Science
Abstract

Abstract We found the hepatic transcription factor Cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) to be expressed in adipose tissue, and selectively downregulated in the more metabolically protective subcutaneous adipose tissue in obese mice and humans. We sought to elucidate the specific role of this factor in adipose biology. CREB3L3 fat-specific knockout mice were fed a high-fat diet to induce obesity and metabolic dysfunction. Additionally, we injected a flip-excision adeno-associated virus directly into the subcutaneous inguinal adipose tissue of Adiponectin-Cre mice to create a depot-specific overexpression model for further assessment. Fat-specific ablation of CREB3L3 enhanced weight gain and insulin resistance following high-fat feeding, as fat-specific knockout mice expended less energy and possessed more inflammatory adipose tissue. Conversely, inguinal fat CREB3L3 overexpression deterred diet-induced obesity and ameliorated metabolic dysfunction. Together, this study highlights the relevance of CREB3L3 in obese adipose tissue and demonstrates its role as a powerful body weight modulator.

Published
2021
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13. Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Author

Anastasia Georgiadi, Valeria Lopez-Salazar, Rabih El- Merahbi, Rhoda Anane Karikari, Xiaochuan Ma, André Mourão, Katarina Klepac, Lea Bühler, Ana Jimena Alfaro, Isabell Kaczmarek, Adam Linford, Madeleen Bosma, Olga Shilkova, Olli Ritvos, Nobuhiro Nakamura, Shigehisa Hirose, Maximilian Lassi, Raffaele Teperino, Juliano Machado, Marcel Scheideler, Arne Dietrich, Arie Geerlof, Annette Feuchtinger, Andreas Blutke, Katrin Fischer, Timo Dirk Müller, Katharina Kessler, Torsten Schöneberg, Doreen Thor, Silke Hornemann, Michael Kruse, Peter Nawroth, Olga Pivovarova-Ramich, Andreas Friedrich Hermann Pfeiffer, Michael Sattler, Matthias Blüher, and Stephan Herzig

Subjects
Science
Abstract

The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.

Published
2021
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14. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021
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15. Higher HbA1c levels associate with lower hippocampal serotonin transporter availability in non-diabetic adults with obesity

Author

Rico Grundmann, Michael Rullmann, Julia Luthardt, Franziska Zientek, Georg-Alexander Becker, Marianne Patt, Mohammed K. Hankir, Matthias Blüher, Osama Sabri, and Swen Hesse

Subjects
Medicine, Science
Abstract

Abstract The current study aimed to investigate whether the in vivo availability of central serotonin reuptake transporters (5-HTT) is associated with plasma levels of glycosylated hemoglobin (HbA1c) in non-diabetic humans with obesity. 5-HTT availability was measured by using positron emission tomography (PET) imaging with the 5-HTT selective radiotracer [11C]DASB in 23 non-diabetic individuals with obesity and 14 healthy, non-obesity controls. Parametric images of binding potential BPND were generated from the PET data and analyzed together with HbA1c levels by using volume of interest analysis for brain areas relevant to appetite control. Voxel-based morphometry (VBM) of individual magnetic resonance imaging data was further performed to correlate grey matter density (GMD) maps with HbA1c. We found significant negative correlations between HbA1c levels and BPND in right and left hippocampus in obesity (r = − 0.717, p

Published
2020
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16. Distinct abdominal and gluteal adipose tissue transcriptome signatures are altered by exercise training in African women with obesity

Author

Pamela A. Nono Nankam, Matthias Blüher, Stephanie Kehr, Nora Klöting, Knut Krohn, Kevin Adams, Peter F. Stadler, Amy E. Mendham, and Julia H. Goedecke

Subjects
Medicine, Science
Abstract

Abstract The differential associations of adipose depots with metabolic risk during obesity have been proposed to be controlled by environmental and genetic factors. We evaluated the regional differences in transcriptome signatures between abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) in obese black South African women and tested the hypothesis that 12-week exercise training alters gene expression patterns in a depot-specific manner. Twelve young women performed 12-weeks of supervised aerobic and resistance training. Pre- and post-intervention measurements included peak oxygen consumption (VO2peak), whole-body composition and unbiased gene expression analysis of SAT depots. VO2peak increased, body weight decreased, and body fat distribution improved with exercise training (p

Published
2020
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17. FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

Author

Farnaz Shamsi, Ruidan Xue, Tian Lian Huang, Morten Lundh, Yang Liu, Luiz O. Leiria, Matthew D. Lynes, Elena Kempf, Chih-Hao Wang, Satoru Sugimoto, Pasquale Nigro, Kathrin Landgraf, Tim Schulz, Yiming Li, Brice Emanuelli, Srinivas Kothakota, Lewis T. Williams, Niels Jessen, Steen Bønløkke Pedersen, Yvonne Böttcher, Matthias Blüher, Antje Körner, Laurie J. Goodyear, Moosa Mohammadi, C. Ronald Kahn, and Yu-Hua Tseng

Subjects
Science
Abstract

Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue. Here the authors show that FGF6 and FGF9 induce UCP1 expression in adipocytes and preadipocytes, via modulation of a transcriptional network that is dissociated from brown adipogenesis.

Published
2020
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18. LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat

Author

Elena Schmidt, Ines Dhaouadi, Isabella Gaziano, Matteo Oliverio, Paul Klemm, Motoharu Awazawa, Gerfried Mitterer, Eduardo Fernandez-Rebollo, Marta Pradas-Juni, Wolfgang Wagner, Philipp Hammerschmidt, Rute Loureiro, Christoph Kiefer, Nils R. Hansmeier, Sajjad Khani, Matteo Bergami, Markus Heine, Evgenia Ntini, Peter Frommolt, Peter Zentis, Ulf Andersson Ørom, Jörg Heeren, Matthias Blüher, Martin Bilban, and Jan-Wilhelm Kornfeld

Subjects
Science
Abstract

Brown adipose tissue (BAT) thermogenesis counteracts obesity and promotes metabolic health. The role of long non-coding RNAs (lncRNAs) in the regulation of this process is not well understood. Here the authors identify a maternally expressed lncRNA, H19, that increases BAT oxidative metabolism and energy expenditure.

Published
2018
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20. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Published
2021
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21. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Janina S. Ried, Janina Jeff M., Audrey Y. Chu, Jennifer L. Bragg-Gresham, Jenny van Dongen, Jennifer E. Huffman, Tarunveer S. Ahluwalia, Gemma Cadby, Niina Eklund, Joel Eriksson, Tõnu Esko, Mary F. Feitosa, Anuj Goel, Mathias Gorski, Caroline Hayward, Nancy L. Heard-Costa, Anne U. Jackson, Eero Jokinen, Stavroula Kanoni, Kati Kristiansson, Zoltán Kutalik, Jari Lahti, Jian'an Luan, Reedik Mägi, Anubha Mahajan, Massimo Mangino, Carolina Medina-Gomez, Keri L. Monda, Ilja M. Nolte, Louis Pérusse, Inga Prokopenko, Lu Qi, Lynda M. Rose, Erika Salvi, Megan T. Smith, Harold Snieder, Alena Stančáková, Yun Ju Sung, Ioanna Tachmazidou, Alexander Teumer, Gudmar Thorleifsson, Pim van der Harst, Ryan W. Walker, Sophie R. Wang, Sarah H. Wild, Sara M. Willems, Andrew Wong, Weihua Zhang, Eva Albrecht, Alexessander Couto Alves, Stephan J. L. Bakker, Cristina Barlassina, Traci M. Bartz, John Beilby, Claire Bellis, Richard N. Bergman, Sven Bergmann, John Blangero, Matthias Blüher, Eric Boerwinkle, Lori L. Bonnycastle, Stefan R. Bornstein, Marcel Bruinenberg, Harry Campbell, Yii-Der Ida Chen, Charleston W. K. Chiang, Peter S. Chines, Francis S Collins, Fracensco Cucca, L Adrienne Cupples, Francesca D’Avila, Eco J .C. de Geus, George Dedoussis, Maria Dimitriou, Angela Döring, Johan G. Eriksson, Aliki-Eleni Farmaki, Martin Farrall, Teresa Ferreira, Krista Fischer, Nita G. Forouhi, Nele Friedrich, Anette Prior Gjesing, Nicola Glorioso, Mariaelisa Graff, Harald Grallert, Niels Grarup, Jürgen Gräßler, Jagvir Grewal, Anders Hamsten, Marie Neergaard Harder, Catharina A. Hartman, Maija Hassinen, Nicholas Hastie, Andrew Tym Hattersley, Aki S. Havulinna, Markku Heliövaara, Hans Hillege, Albert Hofman, Oddgeir Holmen, Georg Homuth, Jouke-Jan Hottenga, Jennie Hui, Lise Lotte Husemoen, Pirro G. Hysi, Aaron Isaacs, Till Ittermann, Shapour Jalilzadeh, Alan L. James, Torben Jørgensen, Pekka Jousilahti, Antti Jula, Johanne Marie Justesen, Anne E. Justice, Mika Kähönen, Maria Karaleftheri, Kay Tee Khaw, Sirkka M. Keinanen-Kiukaanniemi, Leena Kinnunen, Paul B. Knekt, Heikki A. Koistinen, Ivana Kolcic, Ishminder K. Kooner, Seppo Koskinen, Peter Kovacs, Theodosios Kyriakou, Tomi Laitinen, Claudia Langenberg, Alexandra M. Lewin, Peter Lichtner, Cecilia M. Lindgren, Jaana Lindström, Allan Linneberg, Roberto Lorbeer, Mattias Lorentzon, Robert Luben, Valeriya Lyssenko, Satu Männistö, Paolo Manunta, Irene Mateo Leach, Wendy L. McArdle, Barbara Mcknight, Karen L. Mohlke, Evelin Mihailov, Lili Milani, Rebecca Mills, May E. Montasser, Andrew P. Morris, Gabriele Müller, Arthur W. Musk, Narisu Narisu, Ken K. Ong, Ben A. Oostra, Clive Osmond, Aarno Palotie, James S. Pankow, Lavinia Paternoster, Brenda W. Penninx, Irene Pichler, Maria G. Pilia, Ozren Polašek, Peter P. Pramstaller, Olli T Raitakari, Tuomo Rankinen, D. C. Rao, Nigel W. Rayner, Rasmus Ribel-Madsen, Treva K. Rice, Marcus Richards, Paul M. Ridker, Fernando Rivadeneira, Kathy A. Ryan, Serena Sanna, Mark A. Sarzynski, Salome Scholtens, Robert A. Scott, Sylvain Sebert, Lorraine Southam, Thomas Hempel Sparsø, Valgerdur Steinthorsdottir, Kathleen Stirrups, Ronald P. Stolk, Konstantin Strauch, Heather M. Stringham, Morris A. Swertz, Amy J. Swift, Anke Tönjes, Emmanouil Tsafantakis, Peter J. van der Most, Jana V. Van Vliet-Ostaptchouk, Liesbeth Vandenput, Erkki Vartiainen, Cristina Venturini, Niek Verweij, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Judith M. Vonk, Gérard Waeber, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Thomas W. Winkler, Alan F. Wright, Laura M. Yerges-Armstrong, Jing Hua Zhao, M. Carola Zillikens, Dorret I. Boomsma, Claude Bouchard, John C. Chambers, Daniel I. Chasman, Daniele Cusi, Ron T. Gansevoort, Christian Gieger, Torben Hansen, Andrew A. Hicks, Frank Hu, Kristian Hveem, Marjo-Riitta Jarvelin, Eero Kajantie, Jaspal S. Kooner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Andres Metspalu, Inger Njølstad, Claes Ohlsson, Albertine J. Oldehinkel, Lyle J. Palmer, Oluf Pedersen, Markus Perola, Annette Peters, Bruce M. Psaty, Hannu Puolijoki, Rainer Rauramaa, Igor Rudan, Veikko Salomaa, Peter E. H. Schwarz, Alan R. Shudiner, Jan H. Smit, Thorkild I. A. Sørensen, Timothy D. Spector, Kari Stefansson, Michael Stumvoll, Angelo Tremblay, Jaakko Tuomilehto, André G. Uitterlinden, Matti Uusitupa, Uwe Völker, Peter Vollenweider, Nicholas J. Wareham, Hugh Watkins, James F. Wilson, Eleftheria Zeggini, Goncalo R. Abecasis, Michael Boehnke, Ingrid B. Borecki, Panos Deloukas, Cornelia M. van Duijn, Caroline Fox, Leif C. Groop, Iris M. Heid, David J. Hunter, Robert C. Kaplan, Mark I. McCarthy, Kari E. North, Jeffrey R. O'Connell, David Schlessinger, Unnur Thorsteinsdottir, David P. Strachan, Timothy Frayling, Joel N. Hirschhorn, Martina Müller-Nurasyid, and Ruth J. F. Loos

Subjects
Science
Abstract

Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.

Published
2016
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22. Control of diabetic hyperglycaemia and insulin resistance through TSC22D4

Author

Bilgen Ekim Üstünel, Kilian Friedrich, Adriano Maida, Xiaoyue Wang, Anja Krones-Herzig, Oksana Seibert, Anke Sommerfeld, Allan Jones, Tjeerd P. Sijmonsma, Carsten Sticht, Norbert Gretz, Thomas Fleming, Peter P. Nawroth, Wolfgang Stremmel, Adam J. Rose, Mauricio Berriel-Diaz, Matthias Blüher, and Stephan Herzig

Subjects
Science
Abstract

TSC22D4 regulates hepatic lipoprotein production, but has so far mainly been studied in the context of cancer cachexia. Here, the authors show TSC22D4 inhibition improves insulin sensitivity in several mouse models of diabetes, which they attribute at least in part to the induction of secreted LCN13.

Published
2016
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23. The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation

Author

Guifen Qiang, Hyerim Whang Kong, Difeng Fang, Maximilian McCann, Xiuying Yang, Guanhua Du, Matthias Blüher, Jinfang Zhu, and Chong Wee Liew

Subjects
Science
Abstract

Visceral and subcutaneous fat are associated with different metabolic risk, but mediators of such depot specific effects are not very well known. Here the authors identify the transcriptional regulator, TRIP-Br2, as a regulator of endoplasmic reticulum (ER) stress-induced inflammatory responses specifically in visceral fat.

Published
2016
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24. The Gq signalling pathway inhibits brown and beige adipose tissue

Author

Katarina Klepac, Ana Kilić, Thorsten Gnad, Loren M. Brown, Beate Herrmann, Andrea Wilderman, Aileen Balkow, Anja Glöde, Katharina Simon, Martin E. Lidell, Matthias J. Betz, Sven Enerbäck, Jürgen Wess, Marc Freichel, Matthias Blüher, Gabi König, Evi Kostenis, Paul A. Insel, and Alexander Pfeifer

Subjects
Science
Abstract

Brown and beige adipose tissues contribute to organismal energy expenditure by generating heat. Here, Klepac et al. survey G protein-coupled receptors in brown fat and show that Gq-coupled receptors inhibit expression of thermogenic proteins in mice and in human adipocytes.

Published
2016
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25. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Yingchang Lu, Felix R. Day, Stefan Gustafsson, Martin L. Buchkovich, Jianbo Na, Veronique Bataille, Diana L. Cousminer, Zari Dastani, Alexander W. Drong, Tõnu Esko, David M. Evans, Mario Falchi, Mary F. Feitosa, Teresa Ferreira, Åsa K. Hedman, Robin Haring, Pirro G. Hysi, Mark M. Iles, Anne E. Justice, Stavroula Kanoni, Vasiliki Lagou, Rui Li, Xin Li, Adam Locke, Chen Lu, Reedik Mägi, John R. B. Perry, Tune H. Pers, Qibin Qi, Marianna Sanna, Ellen M. Schmidt, William R. Scott, Dmitry Shungin, Alexander Teumer, Anna A. E. Vinkhuyzen, Ryan W. Walker, Harm-Jan Westra, Mingfeng Zhang, Weihua Zhang, Jing Hua Zhao, Zhihong Zhu, Uzma Afzal, Tarunveer Singh Ahluwalia, Stephan J. L. Bakker, Claire Bellis, Amélie Bonnefond, Katja Borodulin, Aron S. Buchman, Tommy Cederholm, Audrey C. Choh, Hyung Jin Choi, Joanne E. Curran, Lisette C. P. G. M. de Groot, Philip L. De Jager, Rosalie A. M. Dhonukshe-Rutten, Anke W. Enneman, Elodie Eury, Daniel S. Evans, Tom Forsen, Nele Friedrich, Frédéric Fumeron, Melissa E. Garcia, Simone Gärtner, Bok-Ghee Han, Aki S. Havulinna, Caroline Hayward, Dena Hernandez, Hans Hillege, Till Ittermann, Jack W. Kent, Ivana Kolcic, Tiina Laatikainen, Jari Lahti, Irene Mateo Leach, Christine G. Lee, Jong-Young Lee, Tian Liu, Youfang Liu, Stéphane Lobbens, Marie Loh, Leo-Pekka Lyytikäinen, Carolina Medina-Gomez, Karl Michaëlsson, Mike A. Nalls, Carrie M. Nielson, Laticia Oozageer, Laura Pascoe, Lavinia Paternoster, Ozren Polašek, Samuli Ripatti, Mark A. Sarzynski, Chan Soo Shin, Nina Smolej Narančić, Dominik Spira, Priya Srikanth, Elisabeth Steinhagen-Thiessen, Yun Ju Sung, Karin M. A. Swart, Leena Taittonen, Toshiko Tanaka, Emmi Tikkanen, Nathalie van der Velde, Natasja M. van Schoor, Niek Verweij, Alan F. Wright, Lei Yu, Joseph M. Zmuda, Niina Eklund, Terrence Forrester, Niels Grarup, Anne U. Jackson, Kati Kristiansson, Teemu Kuulasmaa, Johanna Kuusisto, Peter Lichtner, Jian'an Luan, Anubha Mahajan, Satu Männistö, Cameron D. Palmer, Janina S. Ried, Robert A. Scott, Alena Stancáková, Peter J. Wagner, Ayse Demirkan, Angela Döring, Vilmundur Gudnason, Douglas P. Kiel, Brigitte Kühnel, Massimo Mangino, Barbara Mcknight, Cristina Menni, Jeffrey R. O'Connell, Ben A. Oostra, Alan R. Shuldiner, Kijoung Song, Liesbeth Vandenput, Cornelia M. van Duijn, Peter Vollenweider, Charles C. White, Michael Boehnke, Yvonne Boettcher, Richard S. Cooper, Nita G. Forouhi, Christian Gieger, Harald Grallert, Aroon Hingorani, Torben Jørgensen, Pekka Jousilahti, Mika Kivimaki, Meena Kumari, Markku Laakso, Claudia Langenberg, Allan Linneberg, Amy Luke, Colin A. Mckenzie, Aarno Palotie, Oluf Pedersen, Annette Peters, Konstantin Strauch, Bamidele O. Tayo, Nicholas J. Wareham, David A. Bennett, Lars Bertram, John Blangero, Matthias Blüher, Claude Bouchard, Harry Campbell, Nam H. Cho, Steven R. Cummings, Stefan A. Czerwinski, Ilja Demuth, Rahel Eckardt, Johan G. Eriksson, Luigi Ferrucci, Oscar H. Franco, Philippe Froguel, Ron T. Gansevoort, Torben Hansen, Tamara B. Harris, Nicholas Hastie, Markku Heliövaara, Albert Hofman, Joanne M. Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Paul B. Knekt, Seppo Koskinen, Peter Kovacs, Terho Lehtimäki, Lars Lind, Yongmei Liu, Eric S. Orwoll, Clive Osmond, Markus Perola, Louis Pérusse, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Treva K. Rice, Fernando Rivadeneira, Igor Rudan, Veikko Salomaa, Thorkild I. A. Sørensen, Michael Stumvoll, Anke Tönjes, Bradford Towne, Gregory J. Tranah, Angelo Tremblay, André G. Uitterlinden, Pim van der Harst, Erkki Vartiainen, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Henry Völzke, Mark Walker, Henri Wallaschofski, Sarah Wild, James F. Wilson, Loïc Yengo, D. Timothy Bishop, Ingrid B. Borecki, John C. Chambers, L. Adrienne Cupples, Abbas Dehghan, Panos Deloukas, Ghazaleh Fatemifar, Caroline Fox, Terrence S. Furey, Lude Franke, Jiali Han, David J. Hunter, Juha Karjalainen, Fredrik Karpe, Robert C. Kaplan, Jaspal S. Kooner, Mark I. McCarthy, Joanne M. Murabito, Andrew P. Morris, Julia A. N. Bishop, Kari E. North, Claes Ohlsson, Ken K. Ong, Inga Prokopenko, J. Brent Richards, Eric E. Schadt, Tim D. Spector, Elisabeth Widén, Cristen J. Willer, Jian Yang, Erik Ingelsson, Karen L. Mohlke, Joel N. Hirschhorn, John Andrew Pospisilik, M. Carola Zillikens, Cecilia Lindgren, Tuomas Oskari Kilpeläinen, and Ruth J. F. Loos

Subjects
Science
Abstract

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2016
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26. FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

Author

Yiming Li, Matthew D. Lynes, Lewis T. Williams, Tim J. Schulz, Steen B. Pedersen, Tian Lian Huang, Niels Jessen, Farnaz Shamsi, Laurie J. Goodyear, Morten Lundh, Matthias Blüher, Srinivas Kothakota, Moosa Mohammadi, Yu-Hua Tseng, Ruidan Xue, Chih-Hao Wang, Pasquale Nigro, Satoru Sugimoto, Brice Emanuelli, Antje Körner, Yang Liu, Luiz O. Leiria, Elena Kempf, Kathrin Landgraf, C. Ronald Kahn, and Yvonne Böttcher

Subjects
Fibroblast Growth Factor 9, Male, 0301 basic medicine, Fibroblast Growth Factor 6, Science, General Physics and Astronomy, Adipose tissue, Adipokine, Fibroblast growth factor, Article, General Biochemistry, Genetics and Molecular Biology, TERMOGÊNESE, Mice, 03 medical and health sciences, 0302 clinical medicine, Adipose Tissue, Brown, FGF9, Downregulation and upregulation, Brown adipose tissue, Adipocytes, medicine, Animals, Humans, Obesity, lcsh:Science, Uncoupling Protein 1, Adipogenesis, Multidisciplinary, Chemistry, Thermogenesis, General Chemistry, Cell biology, Mice, Inbred C57BL, stomatognathic diseases, Adipocytes, Brown, 030104 developmental biology, medicine.anatomical_structure, lcsh:Q, Fat metabolism, 030217 neurology & neurosurgery
Abstract

Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism., Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue. Here the authors show that FGF6 and FGF9 induce UCP1 expression in adipocytes and preadipocytes, via modulation of a transcriptional network that is dissociated from brown adipogenesis.

Published
2020

27. Author Correction: Adipose expression of CREB3L3 modulates body weight during obesity

Author

Victoria Gil, Chong Wee Liew, Yanliang Li, Jose Cordoba-Chacon, Marcos D. Munoz, Matthias Blüher, Maximilian A. Mccann, Stephen A. Duncan, and Guifen Qiang

Subjects
medicine.medical_specialty, Multidisciplinary, business.industry, Science, Adipose tissue, Biology, Body weight, medicine.disease, Obesity, Endocrinology, Text mining, Expression (architecture), Internal medicine, medicine, Medicine, business
Published
2021

28. Control of diabetic hyperglycaemia and insulin resistance through TSC22D4

Author

Tjeerd P. Sijmonsma, Wolfgang Stremmel, Peter P. Nawroth, Adam J. Rose, Mauricio Berriel-Diaz, Carsten Sticht, Matthias Blüher, Kilian Friedrich, Stephan Herzig, Allan Jones, Norbert Gretz, Xiaoyue Wang, Adriano Maida, Anke Sommerfeld, Bilgen Ekim Üstünel, Thomas Fleming, Anja Krones-Herzig, and Oksana Seibert

Subjects
Blood Glucose, Male, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Science, General Physics and Astronomy, Type 2 diabetes, Biology, Carbohydrate metabolism, Diabetes Therapy, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Mice, Knockout, Multidisciplinary, Insulin, General Chemistry, medicine.disease, Lipocalins, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation, Liver, Hyperglycemia, Female, Insulin Resistance, Beta cell, Metabolic syndrome, Transcription Factors
Abstract

Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis—at least in part—through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy., TSC22D4 regulates hepatic lipoprotein production, but has so far mainly been studied in the context of cancer cachexia. Here, the authors show TSC22D4 inhibition improves insulin sensitivity in several mouse models of diabetes, which they attribute at least in part to the induction of secreted LCN13.

Published
2016

29. The Gq signalling pathway inhibits brown and beige adipose tissue

Author

Marc Freichel, Evi Kostenis, Katharina Simon, Ana Kilić, Beate Herrmann, Matthias Blüher, Loren M. Brown, Aileen Balkow, Martin E. Lidell, Thorsten Gnad, Sven Enerbäck, Katarina Klepac, Alexander Pfeifer, Jürgen Wess, Paul A. Insel, Matthias J. Betz, Andrea Wilderman, Gabi König, and Anja Glöde

Subjects
0301 basic medicine, medicine.medical_specialty, Adipose Tissue, White, Science, Adipocytes, White, General Physics and Astronomy, Adipose tissue, White adipose tissue, Biology, Article, Ion Channels, General Biochemistry, Genetics and Molecular Biology, Mitochondrial Proteins, Mice, 03 medical and health sciences, Adipose Tissue, Brown, Internal medicine, Brown adipose tissue, medicine, Animals, Humans, Autocrine signalling, Uncoupling Protein 1, PRDM16, Adipogenesis, Multidisciplinary, Cell Differentiation, General Chemistry, Thermogenin, Adipocytes, Brown, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Gq alpha subunit, biology.protein, GTP-Binding Protein alpha Subunits, Gq-G11, Signal Transduction
Abstract

Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the Gq family, and inhibition of Gq signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of Gq signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of Gq signalling in brown adipocytes. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of Gq in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that Gq signalling regulates brown/beige adipocytes and inhibition of Gq signalling may be a novel therapeutic approach to combat obesity., Brown and beige adipose tissues contribute to organismal energy expenditure by generating heat. Here, Klepac et al. survey G protein-coupled receptors in brown fat and show that Gq-coupled receptors inhibit expression of thermogenic proteins in mice and in human adipocytes.

Published
2016

30. The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance

Author

Jérémie Gautheron, Mihael Vucur, Anne T. Schneider, Ilenia Severi, Christoph Roderburg, Sanchari Roy, Matthias Bartneck, Peter Schrammen, Mauricio Berriel Diaz, Josef Ehling, Felix Gremse, Felix Heymann, Christiane Koppe, Twan Lammers, Fabian Kiessling, Niels Van Best, Oliver Pabst, Gilles Courtois, Andreas Linkermann, Stefan Krautwald, Ulf P. Neumann, Frank Tacke, Christian Trautwein, Douglas R. Green, Thomas Longerich, Norbert Frey, Mark Luedde, Matthias Bluher, Stephan Herzig, Mathias Heikenwalder, and Tom Luedde

Subjects
Science
Abstract

The kinase RIPK3 initiates necroptosis, which has been reported to promote inflammation in various pathological conditions. Here, the authors show that genetic ablation of Ripk3results in adipocyte apoptosis and white adipose tissue inflammation in obese mice, which promotes glucose intolerance.

Published
2016
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