28 results on '"Thorsten Gnad"'
Search Results
2. Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity
- Author
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Julia Münzker, Nadine Haase, Andreas Till, Robert Sucher, Sven-Bastiaan Haange, Linda Nemetschke, Thorsten Gnad, Elisabeth Jäger, Jiesi Chen, Sjaak J. Riede, Rima Chakaroun, Lucas Massier, Peter Kovacs, Mario Ost, Ulrike Rolle-Kampczyk, Nico Jehmlich, Juliane Weiner, John T. Heiker, Nora Klöting, Gudrun Seeger, Markus Morawski, Verena Keitel, Alexander Pfeifer, Martin von Bergen, Joerg Heeren, Ute Krügel, and Wiebke K. Fenske
- Subjects
Gastric bypass ,Gut microbiota ,FXR ,TGR5 ,Bile acids ,Taurine metabolism ,Microbial ecology ,QR100-130 - Abstract
Abstract Background Bariatric surgery remains the most effective therapy for adiposity reduction and remission of type 2 diabetes. Although different bariatric procedures associate with pronounced shifts in the gut microbiota, their functional role in the regulation of energetic and metabolic benefits achieved with the surgery are not clear. Methods To evaluate the causal as well as the inherent therapeutic character of the surgery-altered gut microbiome in improved energy and metabolic control in diet-induced obesity, an antibiotic cocktail was used to eliminate the gut microbiota in diet-induced obese rats after gastric bypass surgery, and gastric bypass-shaped gut microbiota was transplanted into obese littermates. Thorough metabolic profiling was combined with omics technologies on samples collected from cecum and plasma to identify adaptions in gut microbiota-host signaling, which control improved energy balance and metabolic profile after surgery. Results In this study, we first demonstrate that depletion of the gut microbiota largely reversed the beneficial effects of gastric bypass surgery on negative energy balance and improved glucolipid metabolism. Further, we show that the gastric bypass-shaped gut microbiota reduces adiposity in diet-induced obese recipients by re-activating energy expenditure from metabolic active brown adipose tissue. These beneficial effects were linked to improved glucose homeostasis, lipid control, and improved fatty liver disease. Mechanistically, these effects were triggered by modulation of taurine metabolism by the gastric bypass gut microbiota, fostering an increased abundance of intestinal and circulating taurine-conjugated bile acid species. In turn, these bile acids activated gut-restricted FXR and systemic TGR5 signaling to stimulate adaptive thermogenesis. Conclusion Our results establish the role of the gut microbiome in the weight loss and metabolic success of gastric bypass surgery. We here identify a signaling cascade that entails altered bile acid receptor signaling resulting from a collective, hitherto undescribed change in the metabolic activity of a cluster of bacteria, thereby readjusting energy imbalance and metabolic disease in the obese host. These findings strengthen the rationale for microbiota-targeted strategies to improve and refine current therapies of obesity and metabolic syndrome. Video Abstract Graphical abstract Bariatric Surgery (i.e. RYGB) or the repeated fecal microbiota transfer (FMT) from RYGB donors into DIO (diet-induced obesity) animals induces shifts in the intestinal microbiome, an effect that can be impaired by oral application of antibiotics (ABx). Our current study shows that RYGB-dependent alterations in the intestinal microbiome result in an increase in the luminal and systemic pool of Taurine-conjugated Bile acids (TCBAs) by various cellular mechanisms acting in the intestine and the liver. TCBAs induce signaling via two different receptors, farnesoid X receptor (FXR, specifically in the intestines) and the G-protein-coupled bile acid receptor TGR5 (systemically), finally resulting in metabolic improvement and advanced weight management. BSH, bile salt hydrolase; BAT brown adipose tissue.
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- 2022
- Full Text
- View/download PDF
3. EBI2 is a negative modulator of brown adipose tissue energy expenditure in mice and human brown adipocytes
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Francesca Copperi, Inna Schleis, Martin Roumain, Giulio G. Muccioli, Stefano Casola, Martin Klingenspor, Alexander Pfeifer, and Thorsten Gnad
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Biology (General) ,QH301-705.5 - Abstract
Francesca Copperi et al. evaluate the role of the Gi-protein coupled receptor, EBI2, on regulation of thermogenic activity in murine and human adipocytes. They report that loss of Ebi2 in mice increases brown adipocyte energy expenditure in response to cold exposure, providing insight into ways to potentially modulate energy expenditure in humans.
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- 2022
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- View/download PDF
4. Lack of Gαi2 proteins in adipocytes attenuates diet-induced obesity
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Veronika Leiss, Annika Schönsiegel, Thorsten Gnad, Johannes Kerner, Jyotsna Kaur, Tina Sartorius, Jürgen Machann, Fritz Schick, Lutz Birnbaumer, Hans-Ulrich Häring, Alexander Pfeifer, and Bernd Nürnberg
- Subjects
Adipocytes ,brown adipose tissue ,Gnai2 ,G proteins ,High fat diet ,Insulin ,Internal medicine ,RC31-1245 - Abstract
Objectives: Typically, obesity results from an inappropriate balance between energy uptake from nutrient consumption and burning of calories, which leads to a pathological increase in fat mass. Obesity is a major cause of insulin resistance and diabetes. Inhibitory G proteins (Gαi) form a subfamily that is involved in the regulation of adipose tissue function. Among the three Gαi members, i.e. Gαi1, Gαi2, Gαi3, the Gαi2, protein is predominantly expressed in adipose tissue. However, the functions of the Gαi2 isoform in adipose tissue and its impact on the development of obesity are poorly understood. Methods: By using AdipoqCreERT2 mice, we generated adipocyte-specific Gnai2-deficient mice to study Gαi2 function, specifically in white and brown adipocytes. These mice were fed either a control diet (CD) or a high fat diet (HFD). Mice were examined for obesity development, insulin resistance and glucose intolerance. We examined adipocyte morphology and the development of inflammation in the white adipose tissue. Finally, intracellular cAMP levels as an indicator of Gαi signaling and glycerol release as an indicator of lipolysis rates were measured to verify the impact of Gαi2 on the signaling pathway in brown and white adipocytes. Results: An adipocyte-specific deficiency of Gαi2 significantly reduced diet-induced obesity, leading to decreased fat masses, smaller adipocytes and decreased inflammation in the white adipose tissue relative to littermate controls. Concurrently, oxygen consumption of brown adipocytes and in vivo measured energy expenditure were significantly enhanced. In addition, glucose tolerance and insulin sensitivity of HFD-fed adipocyte-specific Gnai2-deficient mice were improved compared to the respective controls. In the absence of Gαi2, adrenergic stimulation of intracellular adipocyte cAMP levels was increased, which correlated with increased lipolysis and energy expenditure. Conclusion: We conclude that adipocyte Gαi2 is a major regulator of adipocyte lipid content in diet-induced obesity by inhibiting adipocyte lipolysis in a cAMP-dependent manner resulting in increased energy expenditure.
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- 2020
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5. Divergent effects of a designer natriuretic peptide CD-NP in the regulation of adipose tissue and metabolism
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Anja Glöde, Jennifer Naumann, Thorsten Gnad, Valentina Cannone, Ana Kilic, John C. Burnett, Jr., and Alexander Pfeifer
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Internal medicine ,RC31-1245 - Abstract
Objective: Obesity is defined as an abnormal increase in white adipose tissue (WAT) and is a major risk factor for type 2 diabetes and cardiovascular disease. Brown adipose tissue (BAT) dissipates energy and correlates with leanness. Natriuretic peptides have been shown to be beneficial for brown adipocyte differentiation and browning of WAT. Methods: Here, we investigated the effects of an optimized designer natriuretic peptide (CD-NP) on murine adipose tissues in vitro and in vivo. Results: In murine brown and white adipocytes, CD-NP activated cGMP production, promoted adipogenesis, and increased thermogenic markers. Consequently, mice treated for 10 days with CD-NP exhibited increased “browning” of WAT. To study CD-NP effects on diet-induced obesity (DIO), we delivered CD-NP for 12 weeks. Although CD-NP reduced inflammation in WAT, CD-NP treated DIO mice exhibited a significant increase in body mass, worsened glucose tolerance, and hepatic steatosis. Long-term CD-NP treatment resulted in an increased expression of the NP scavenging receptor (NPR-C) and decreased lipolytic activity. Conclusions: NP effects differed depending on the duration of treatment raising questions about the rational of natriuretic peptide treatment in obese patients. Keywords: Natriuretic peptides, cGMP, Adipocytes, Browning, Diet-induced obesity
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- 2017
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6. The Gq signalling pathway inhibits brown and beige adipose tissue
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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
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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.
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- 2016
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7. AdipoQ—a simple, open-source software to quantify adipocyte morphology and function in tissues and in vitro
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Katharina Sieckmann, Nora Winnerling, Mylene Huebecker, Philipp Leyendecker, Dalila Juliana Silva Ribeiro, Thorsten Gnad, Alexander Pfeifer, Dagmar Wachten, and Jan N. Hansen
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Adipose Tissue, Brown ,Adipocytes ,Lipid Droplets ,Cell Biology ,Lipids ,Molecular Biology ,Software - Abstract
The different adipose tissues (ATs) can be distinguished according to their function. For example, white AT stores energy in form of lipids, whereas brown AT dissipates energy in the form of heat. These functional differences are represented in the respective adipocyte morphology; whereas white adipocytes contain large, unilocular lipid droplets, brown adipocytes contain smaller, multilocular lipid droplets. However, an automated, image analysis pipeline to comprehensively analyze adipocytes in vitro in cell culture as well as ex vivo in tissue sections is missing. We here present AdipoQ, an open-source software implemented as ImageJ plugins that allows us to analyze adipocytes in tissue sections and in vitro after histological and/or immunofluorescent labeling. AdipoQ is compatible with different imaging modalities and staining methods, allows batch processing of large datasets and simple post-hoc analysis, provides a broad band of parameters, and allows combining multiple fluorescent readouts. Therefore AdipoQ is of immediate use not only for basic research but also for clinical diagnosis.
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- 2022
8. Cold-induced expression of a truncated Adenylyl Cyclase 3 acts as rheostat to brown fat function
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Sajjad Khani, Hande Topel, Ajeetha Josephrajan, Bjørk Ditlev Marcher Larsen, Ana Rita Albuquerque de Almeida Tavanez, Michael James Gaudry, Philipp Leyendecker, Natasa Stanic, Isabella Gaziano, Nils Rouven Hansmeier, Elena Schmidt, Paul Klemm, Lara-Marie Vagliano, Christoph Andreas Engelhard, Søren Nielsen, Naja Zenius Jespersen, Rizwan Rehimi, Sabrina Gohlke, Peter Frommolt, Thorsten Gnad, Alvaro Rada-Iglesias, Marta Pradas-Juni, Tim Julius Schulz, Frank Thomas Wunderlich, Alexander Pfeifer, Martin Jastroch, Dagmar Wachten, and Jan-Wilhelm Kornfeld
- Abstract
Promoting brown adipose tissue (BAT) activity has been recognized as innovative therapeutic approach to improve obesity and metabolic disease. Whilst the molecular circuitry underlying thermogenic activation of BAT is well understood, the processes underlying rheostatic regulation of BAT to maintain homeostasis and avoid excessive energy dissipation remain ill-defined. Increasing cyclic AMP (cAMP) biosynthesis is key for BAT activation. Here, we demonstrate that ADCY3, an adenylyl cyclase whose expression is induced during cold exposure and regulates cAMP homeostasis in thermogenic fat, is dispensable for BAT function in lean mice, but becomes critical during obesity. Furthermore, by combining RNA-seq with epigenomic H3K4me3 profiling, we detected a novel, cold-inducible promoter that generates a 5’ truncated Adcy3-at mRNA isoform, Adcy3-at. Mice lacking only Adcy3-at, but not full-length Adcy3, displayed increased energy expenditure already under lean conditions and were protected against obesity and ensuing metabolic imbalances. Subcellularly, translated ADCY3-AT proteins are retained in the endoplasmic reticulum (ER), did not translocate to the cell membrane, and lacked enzymatic activity. By interacting with ADCY3, ADCY3-AT retained ADCY3 in the ER and, thereby, reduced the plasma membrane pool of ADCYs available for G-protein mediated cAMP synthesis. Thereby, ADCY3-AT acts as a signaling rheostat in BAT, limiting adverse consequences of uncurbed cAMP activity after long-term BAT activation. Adcy3-at induction was driven by a cold-induced, truncated isoform of the transcriptional cofactor PPARGC1A (PPARG Coactivator 1 Alpha, PPARGC1A-AT). Expression of Ppargc1a-at and Adcy3-at are evolutionary conserved, indicating that transcriptional rewiring by commissioning of alternative promoters is key for thermogenic fat function.
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- 2022
9. Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity
- Author
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Julia, Münzker, Nadine, Haase, Andreas, Till, Robert, Sucher, Sven-Bastiaan, Haange, Linda, Nemetschke, Thorsten, Gnad, Elisabeth, Jäger, Jiesi, Chen, Sjaak J, Riede, Rima, Chakaroun, Lucas, Massier, Peter, Kovacs, Mario, Ost, Ulrike, Rolle-Kampczyk, Nico, Jehmlich, Juliane, Weiner, John T, Heiker, Nora, Klöting, Gudrun, Seeger, Markus, Morawski, Verena, Keitel, Alexander, Pfeifer, Martin, von Bergen, Joerg, Heeren, Ute, Krügel, and Wiebke K, Fenske
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Blood Glucose ,Bile Acids ,Fxr ,Gastric Bypass ,Gut Microbiota ,Tgr5 ,Taurine Metabolism ,Taurine ,Microbiota ,Thermogenesis ,Diet ,Rats ,Receptors, G-Protein-Coupled ,Bile Acids and Salts ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Animals ,Obesity - Abstract
BACKGROUND: Bariatric surgery remains the most effective therapy for adiposity reduction and remission of type 2 diabetes. Although different bariatric procedures associate with pronounced shifts in the gut microbiota, their functional role in the regulation of energetic and metabolic benefits achieved with the surgery are not clear. METHODS: To evaluate the causal as well as the inherent therapeutic character of the surgery-altered gut microbiome in improved energy and metabolic control in diet-induced obesity, an antibiotic cocktail was used to eliminate the gut microbiota in diet-induced obese rats after gastric bypass surgery, and gastric bypass-shaped gut microbiota was transplanted into obese littermates. Thorough metabolic profiling was combined with omics technologies on samples collected from cecum and plasma to identify adaptions in gut microbiota-host signaling, which control improved energy balance and metabolic profile after surgery. RESULTS: In this study, we first demonstrate that depletion of the gut microbiota largely reversed the beneficial effects of gastric bypass surgery on negative energy balance and improved glucolipid metabolism. Further, we show that the gastric bypass-shaped gut microbiota reduces adiposity in diet-induced obese recipients by re-activating energy expenditure from metabolic active brown adipose tissue. These beneficial effects were linked to improved glucose homeostasis, lipid control, and improved fatty liver disease. Mechanistically, these effects were triggered by modulation of taurine metabolism by the gastric bypass gut microbiota, fostering an increased abundance of intestinal and circulating taurine-conjugated bile acid species. In turn, these bile acids activated gut-restricted FXR and systemic TGR5 signaling to stimulate adaptive thermogenesis. CONCLUSION: Our results establish the role of the gut microbiome in the weight loss and metabolic success of gastric bypass surgery. We here identify a signaling cascade that entails altered bile acid receptor signaling resulting from a collective, hitherto undescribed change in the metabolic activity of a cluster of bacteria, thereby readjusting energy imbalance and metabolic disease in the obese host. These findings strengthen the rationale for microbiota-targeted strategies to improve and refine current therapies of obesity and metabolic syndrome. Video Abstract Bariatric Surgery (i.e. RYGB) or the repeated fecal microbiota transfer (FMT) from RYGB donors into DIO (diet-induced obesity) animals induces shifts in the intestinal microbiome, an effect that can be impaired by oral application of antibiotics (ABx). Our current study shows that RYGB-dependent alterations in the intestinal microbiome result in an increase in the luminal and systemic pool of Taurine-conjugated Bile acids (TCBAs) by various cellular mechanisms acting in the intestine and the liver. TCBAs induce signaling via two different receptors, farnesoid X receptor (FXR, specifically in the intestines) and the G-protein-coupled bile acid receptor TGR5 (systemically), finally resulting in metabolic improvement and advanced weight management. BSH, bile salt hydrolase; BAT brown adipose tissue.
- Published
- 2022
10. EBI2 is a negative modulator of brown adipose tissue energy expenditure in mice and human brown adipocytes
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Francesca, Copperi, Inna, Schleis, Martin, Roumain, Giulio G, Muccioli, Stefano, Casola, Martin, Klingenspor, Alexander, Pfeifer, Thorsten, Gnad, and UCL - SSS/LDRI - Louvain Drug Research Institute
- Subjects
Mice ,Norepinephrine ,Adipocytes, Brown ,Adipose Tissue, Brown ,Animals ,Humans ,Thermogenesis ,Energy Metabolism ,Receptors, G-Protein-Coupled - Abstract
Pharmacological activation of brown adipose tissue (BAT) is an attractive approach for increasing energy expenditure to counteract obesity. Given the side-effects of known activators of BAT, we studied inhibitors of BAT as a novel, alternative concept to regulate energy expenditure. We focused on G-protein-coupled receptors that are one of the major targets of clinically used drugs. Here, we identify GPR183, also known as EBI2, as the most highly expressed inhibitory G-protein-coupled receptor in BAT among the receptors examined. Activation of EBI2 using its endogenous ligand 7α,25-dihydroxycholesterol significantly decreases BAT-mediated energy expenditure in mice. In contrast, mice deficient for EBI2 show increased energy dissipation in response to cold. Interestingly, only thermogenic adipose tissue depots - BAT and subcutaneous white adipose tissue -respond to 7α,25-dihydroxycholesterol treatment/EBI2 activation but not gonadal white fat, which has the lowest thermogenic capacity. EBI2 activation in brown adipocytes significantly reduces norepinephrine-induced cAMP production, whereas pharmacological inhibition or genetic ablation of EBI2 results in an increased response. Importantly, EBI2 significantly inhibits norepinephrine-induced activation of human brown adipocytes. Our data identify the 7α,25-dihydroxycholesterol/EBI2 signaling pathway as a so far unknown BAT inhibitor. Understanding the inhibitory regulation of BAT might lead to novel pharmacological approaches to increase the activity of thermogenic adipose tissue and whole body energy expenditure in humans.
- Published
- 2022
11. Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis
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Seth McGonigle, Susanne Mandrup, Olivia Sveidahl Johansen, Laia Reverte-Salisa, Rudolf Zechner, Lasse K. Markussen, Thomas Nielsen, Eline N. Kuipers, Andreas Kjaer, Maria Razzoli, Alexander Pfeifer, Jakob Bondo Hansen, Cheryl Cero, Alessandro Bartolomucci, James G. Granneman, Brice Emanuelli, Raymond E. Soccio, Morten Lundh, Thue Walter Schwartz, Søren Nielsen, Wenfei Sun, Dan Ploug Christensen, Hua Dong, Christa Broholm, Thorsten Gnad, Nienke Willemsen, Camilla Scheele, William Orchard, Oksana Dmytriyeva, Iuliia Karavaeva, Patrick C.N. Rensen, Marie S. Isidor, Sander Kooijman, Niels Grarup, Mikkel Frost, Cecilie Mørch Hallgren, Davide Calebiro, Tao Ma, Naja Z. Jespersen, M. Madan Babu, Mikael Rydén, Shannon L. O'Brien, Carsten H. Nielsen, Renate Schreiber, Zachary Gerhart-Hines, Jacob B. Hansen, Jonas T. Treebak, Yachen Shen, Torben Hansen, Oluf Pedersen, and Elahu G. Sustarsic
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endocrine system ,Sympathetic Nervous System ,Transcription, Genetic ,Adrenergic receptor ,Lipolysis ,Adipose tissue ,GPR3 ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,GPCR ,Adipose Tissue, Brown ,constitutively active ,Chlorocebus aethiops ,Brown adipose tissue ,energy expenditure ,Adipocytes ,medicine ,Animals ,Humans ,G protein-coupled receptor ,Receptor ,Cells, Cultured ,Constitutive Androstane Receptor ,030304 developmental biology ,adrenergic receptor ,0303 health sciences ,Thermogenesis ,brown adipose tissue ,thermogenesis ,Dietary Fats ,Cell biology ,Cold Temperature ,Mice, Inbred C57BL ,Phenotype ,medicine.anatomical_structure ,COS Cells ,lipolysis ,transcription ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3., Cell, 184 (13), ISSN:0092-8674, ISSN:1097-4172
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- 2021
12. Regulation of Brown Adipose Tissue and Beige Fat by the Adenosine A2B Receptor 8.5.5
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Thorsten Gnad and Alexander Pfeifer
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medicine.medical_specialty ,medicine.anatomical_structure ,Endocrinology ,Chemistry ,Internal medicine ,Brown adipose tissue ,Genetics ,medicine ,Molecular Biology ,Biochemistry ,Adenosine A2B receptor ,Biotechnology - Published
- 2021
13. Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity
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Thorsten Gnad, Gemma Navarro, Minna Lahesmaa, Laia Reverte-Salisa, Francesca Copperi, Arnau Cordomi, Jennifer Naumann, Aileen Hochhäuser, Saskia Haufs-Brusberg, Daniela Wenzel, Frank Suhr, Naja Zenius Jespersen, Camilla Scheele, Volodymyr Tsvilovskyy, Christian Brinkmann, Joern Rittweger, Christian Dani, Mathias Kranz, Winnie Deuther-Conrad, Holger K. Eltzschig, Tarja Niemi, Markku Taittonen, Peter Brust, Pirjo Nuutila, Leonardo Pardo, Bernd K. Fleischmann, Matthias Blüher, Rafael Franco, Wilhelm Bloch, Kirsi A. Virtanen, and Alexander Pfeifer
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Physiology ,Cell Biology ,Molecular Biology - Published
- 2022
14. Combination of phosphodiesterase‐5‐inhibitors and beta blockers improves experimental portal hypertension and erectile dysfunction
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Patrick S. Kamath, Carlo Alessandria, Arnulf Ferlitsch, Jonel Trebicka, Frank Erhard Uschner, Thomas Reiberger, Rafael Paternostro, Thorsten Gnad, Cristina Ortiz, Sabine Klein, Kathleen Glückert, Christoph Boesecke, Katharina Schwarzkopf, Mattias Mandorfer, Wolfgang Kreisel, Fernando Magdaleno, Alexander Pfeifer, Robert Schierwagen, and Tilman Sauerbruch
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Male ,Mean arterial pressure ,medicine.medical_specialty ,Cirrhosis ,Portal venous pressure ,Propranolol ,Liver Cirrhosis, Experimental ,Gastroenterology ,Rats, Sprague-Dawley ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Erectile Dysfunction ,Internal medicine ,Hypertension, Portal ,Medicine ,Animals ,Humans ,ddc:610 ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Udenafil ,Hepatology ,business.industry ,Phosphodiesterase 5 Inhibitors ,medicine.disease ,Portal Pressure ,3. Good health ,Rats ,030220 oncology & carcinogenesis ,cGMP-specific phosphodiesterase type 5 ,Portal hypertension ,030211 gastroenterology & hepatology ,business ,medicine.drug - Abstract
Background & aims Phosphodiesterase-5 inhibitors (PDE-5-I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side-effects have been reported. Non-selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE-5-I with NSBB and its impact on PH and ED in experimental cirrhosis. Methods ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile-duct-ligation or carbon-tetrachloride intoxication in rats. Corpus cavernosum pressure - a surrogate of ED -, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE-5 signalling were analysed using PCR and western Blot. Results ED in humans was related to severity of liver disease and to NSBB treatment. PDE-5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side-effects. Conclusions ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE-5-I and NSBB improves ED and PH in experimental cirrhosis.
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- 2020
- Full Text
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15. Impact of obesity and aging on crestal alveolar bone height in mice
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James Deschner, Marjan Nokhbehsaim, Anna Damanaki, Thorsten Gnad, Svenja Memmert, Alexander Pfeifer, and Abhishek Sanyal
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Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,Normal diet ,Alveolar Bone Loss ,Gingiva ,Gene Expression ,Mandible ,Diet, High-Fat ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Alveolar Process ,Maxilla ,medicine ,Animals ,Obesity ,Nicotinamide Phosphoribosyltransferase ,Dental alveolus ,Periodontitis ,Adiponectin ,business.industry ,X-Ray Microtomography ,030206 dentistry ,General Medicine ,Periodontium ,medicine.disease ,Molar ,Mice, Inbred C57BL ,Cementoenamel junction ,030104 developmental biology ,Endocrinology ,Cyclooxygenase 2 ,Cytokines ,Crest ,Inflammation Mediators ,Anatomy ,business ,Developmental Biology - Abstract
Obesity and aging are associated with periodontitis, which represents a chronic inflammatory disease of the tooth-supporting tissues, i.e. the periodontium. However, if both risk factors also have a negative impact on crestal alveolar bone in a clinically healthy periodontium, has yet to be elucidated and was analyzed in this in-vivo study. Eight C57BL/6 mice were fed a normal diet during the entire study. Half of these mice were sacrificed at week 19 (group 1: younger lean mice), whereas the other half of the animals were sacrificed at week 25 (group 2: older lean mice). In addition, four mice were fed a high-fat diet until their sacrifice at week 19 (group 3: younger obese mice). Mandibles and maxillae were scanned by micro-computed tomography and, subsequently, the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) at all molars was determined. Levels of interleukin-6, cyclooxygenase-2, visfatin and adiponectin in gingival samples were quantified by real-time PCR. For statistical analyses, the Mann-Whitney-U test was applied (p
- Published
- 2018
16. Divergent effects of a designer natriuretic peptide CD-NP in the regulation of adipose tissue and metabolism
- Author
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Ana Kilić, Thorsten Gnad, John C. Burnett, Valentina Cannone, Jennifer Naumann, Anja Glöde, and Alexander Pfeifer
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0301 basic medicine ,Male ,medicine.medical_specialty ,lcsh:Internal medicine ,medicine.drug_class ,Adipose Tissue, White ,Adipocytes, White ,Adipose tissue ,Inflammation ,White adipose tissue ,Biology ,Brief Communication ,03 medical and health sciences ,Mice ,Adipose Tissue, Brown ,Internal medicine ,Brown adipose tissue ,medicine ,Natriuretic peptide ,Adipocytes ,Animals ,Natriuretic peptides ,Obesity ,Receptor ,lcsh:RC31-1245 ,Molecular Biology ,Elapid Venoms ,Adipogenesis ,Diet-induced obesity ,Natriuretic Peptide, C-Type ,Thermogenesis ,Cell Biology ,medicine.disease ,Diet ,cGMP ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Adipocytes, Brown ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Browning ,Steatosis ,medicine.symptom - Abstract
Objective Obesity is defined as an abnormal increase in white adipose tissue (WAT) and is a major risk factor for type 2 diabetes and cardiovascular disease. Brown adipose tissue (BAT) dissipates energy and correlates with leanness. Natriuretic peptides have been shown to be beneficial for brown adipocyte differentiation and browning of WAT. Methods Here, we investigated the effects of an optimized designer natriuretic peptide (CD-NP) on murine adipose tissues in vitro and in vivo. Results In murine brown and white adipocytes, CD-NP activated cGMP production, promoted adipogenesis, and increased thermogenic markers. Consequently, mice treated for 10 days with CD-NP exhibited increased “browning” of WAT. To study CD-NP effects on diet-induced obesity (DIO), we delivered CD-NP for 12 weeks. Although CD-NP reduced inflammation in WAT, CD-NP treated DIO mice exhibited a significant increase in body mass, worsened glucose tolerance, and hepatic steatosis. Long-term CD-NP treatment resulted in an increased expression of the NP scavenging receptor (NPR-C) and decreased lipolytic activity. Conclusions NP effects differed depending on the duration of treatment raising questions about the rational of natriuretic peptide treatment in obese patients., Highlights • The optimized designer natriuretic peptide CD-NP promotes adipogenesis. • Duration of treatment is decisive: short-term promotes browning whereas long-term treatment exacerbates obesity and diabetes. • Long-term CD-NP treatment reduces WAT inflammation and increases adiponectin expression.
- Published
- 2017
17. A2A R‐induced transcriptional deregulation in astrocytes: An in vitro study
- Author
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Maria Angeliki S. Pavlou, Kevin Carvalho, Gaurav Jain, Didier Vieau, Patrícia I. Santos, Lucrezia Cellai, Thorsten Gnad, David Blum, Tiago F. Outeiro, Luc Buée, Andre Fischer, Alexander Pfeifer, Isabel Paiva, Department of Experimental Neurodegeneration [Göttingen, Germany], University Medical Center Göttingen (UMG), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases [Göttingen, Germany], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institute of Pharmacology and Toxicology [Bonn, Germany], University of Bonn, Max Planck Institute for Experimental Medicine [Göttingen, Germany], Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], ANR (GRAND, SPREADTAU, ADORATAU & ADORASTrAU) DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) Fondation pour la Recherche Médicale, Vaincre Alzheimer, Fondation Plan Alzheimer Inserm, CNRS, Université Lille, Lille Métropole Communauté Urbaine, Région Hauts‐de‐France, DN2M programs d'investissements d'avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) SFB1286 project B6., ANR-14-CE13-0031,SPREADTAU,Transfert différentiel intercellulaire des assemblages de Tau(2014), ANR-12-MALZ-0001,ADORATAU,Récepteurs A2A et Tauopathie(2012), ANR-18-CE16-0008,ADORASTrAU,Contribution des astrocytes aux troubles cognitifs induits par la protéine Tau neuronale dans la maladie d'Alzheimer(2018), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Universität Bonn = University of Bonn, Blum, David, Appel à projets générique - Transfert différentiel intercellulaire des assemblages de Tau - - SPREADTAU2014 - ANR-14-CE13-0031 - Appel à projets générique - VALID, Maladie d'Alzheimer et Maladies Apparentées - Récepteurs A2A et Tauopathie - - ADORATAU2012 - ANR-12-MALZ-0001 - MALZ - VALID, and APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des astrocytes aux troubles cognitifs induits par la protéine Tau neuronale dans la maladie d'Alzheimer - - ADORASTrAU2018 - ANR-18-CE16-0008 - AAPG2018 - VALID
- Subjects
0301 basic medicine ,metabolism [Receptor, Adenosine A2A] ,Adenosine A2A receptor ,drug effects [Astrocytes] ,Biology ,genetics [Receptor, Adenosine A2A] ,SCH-58261 ,Transcriptome ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,astrocyte ,Downregulation and upregulation ,drug effects [Gene Regulatory Networks] ,medicine ,Animals ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,ddc:610 ,Receptor ,physiology [Gene Regulatory Networks] ,Cells, Cultured ,adenosine A2A receptor ,Neurodegeneration ,neurodegeneration ,SCH 58261 ,pharmacology [Adenosine A2 Receptor Antagonists] ,physiology [Astrocytes] ,medicine.disease ,Astrogliosis ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Animals, Newborn ,transcriptional deregulation ,physiology [Transcription, Genetic] ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,drug effects [Transcription, Genetic] ,030217 neurology & neurosurgery ,Astrocyte - Abstract
International audience; Adenosine A2A receptors (A2A R) are modulators of various physiological processes essential for brain homeostasis and fine synaptic tuning. In certain neurodegenerative conditions, notably Alzheimer's disease (AD), A2A Rs are pathologically upregulated in neurons but also in astrocytes. In that context, the use of A2A Rs inhibitors, normalizing impaired receptor function, is seen as a potential therapeutic strategy. However, the impact of A2A R alterations, particularly in astrocytes, is not fully understood. Here, we investigated the effect of A2A R overexpression on transcriptional deregulation in primary astrocytic cultures. By performing whole transcriptome analysis, we found that A2A R overexpression promotes robust transcriptional changes, mostly affecting immune response, angiogenesis, and cell activation-related genes. Importantly, we observed that treatment with SCH58261, a selective A2A R antagonist, restored the expression levels of several inflammatory and astrocytic activation-related genes, such as Interleukin-1beta and vimentin. This supports the notion that A2A R blockade could restore some astrocytic dysfunctions associated with abnormal A2A R expression, further arguing for a potential beneficial impact of receptor antagonists in A2A R-induced transcriptional deregulation, inflammation, and astrogliosis. Overall, our findings provide novel insights into the putative impact of A2A R overexpression on transcriptional deregulation in astrocytes, thereby opening novel avenues for the use of A2A R antagonists as potential therapeutic strategy in neurodegenerative diseases.
- Published
- 2019
18. A
- Author
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Isabel, Paiva, Kévin, Carvalho, Patrícia, Santos, Lucrezia, Cellai, Maria Angeliki S, Pavlou, Gaurav, Jain, Thorsten, Gnad, Alexander, Pfeifer, Didier, Vieau, André, Fischer, Luc, Buée, Tiago F, Outeiro, and David, Blum
- Subjects
Mice ,Animals, Newborn ,Receptor, Adenosine A2A ,Transcription, Genetic ,Astrocytes ,Animals ,Gene Regulatory Networks ,Cells, Cultured ,Adenosine A2 Receptor Antagonists - Abstract
Adenosine A
- Published
- 2018
19. A novel thermoregulatory role for PDE10A in mouse and human adipocytes
- Author
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Nora Klöting, Peter Brust, Thorsten Gnad, Sally Wagner, John T. Heiker, Mathias Kranz, Swen Hesse, Juliane Weiner, Winnie Deuther-Conrad, Matthias Blüher, Mohammed K. Hankir, Alexander Pfeifer, Osama Sabri, Karen Steinhoff, Felix Bronisch, Julia Luthardt, John Seibyl, and Wiebke Fenske
- Subjects
0301 basic medicine ,medicine.medical_specialty ,obesity ,Adipose tissue ,Mice, Obese ,White adipose tissue ,Biology ,Energy homeostasis ,03 medical and health sciences ,Mice ,Internal medicine ,Brown adipose tissue ,Gene expression ,energy expenditure ,medicine ,Adipocytes ,Animals ,Humans ,Enzyme Inhibitors ,Research Articles ,PDE10A ,Phosphoric Diester Hydrolases ,Body Weight ,Phosphodiesterase ,Thermogenesis ,Magnetic Resonance Imaging ,adipose tissue ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,PET ,Metabolism ,Positron-Emission Tomography ,Quinolines ,Molecular Medicine ,Pyrazoles ,Research Article - Abstract
Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small‐animal PET/MRI and the novel radioligand [18F]‐AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP‐10 recruited BAT and potentiated thermogenesis in vivo . In diet‐induced obese mice, chronic administration of MP‐10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP‐10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes. ![][1] PDE inhibitors hold promise for the treatment of obesity due to their ability to induce a thermogenic program in adipocytes. This study reveals that the PDE10A inhibitor MP‐10 has thermoregulatory effects on mouse and human white and brown adipocytes. EMBO Mol Med (2016) 8: 796–812 [1]: /embed/graphic-1.gif
- Published
- 2016
20. The Gq signalling pathway inhibits brown and beige adipose tissue
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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
21. Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity
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Aileen Hochhäuser, Camilla Scheele, Christian Dani, Thorsten Gnad, Frank Suhr, Saskia Haufs-Brusberg, Volodymyr Tsvilovskyy, Peter Brust, Arnau Cordomí, Minna Lahesmaa, Wilhelm Bloch, Markku Taittonen, Matthias Blüher, Mathias Kranz, Leonardo Pardo, Daniela Wenzel, Holger K. Eltzschig, Laia Reverte-Salisa, Francesca Copperi, Alexander Pfeifer, Gemma Navarro, Rafael Franco, Tarja Niemi, Jennifer Naumann, Pirjo Nuutila, Winnie Deuther-Conrad, Christian Brinkmann, Bernd K. Fleischmann, Naja Z. Jespersen, Joern Rittweger, and Kirsi A. Virtanen
- Subjects
Male ,0301 basic medicine ,Aging ,muscle ,Physiology ,Adipose tissue ,BEIGE ADIPOCYTES ,White adipose tissue ,Population aging ,Mice ,GPCR ,Regulació del metabolisme ,0302 clinical medicine ,FUNCTIONAL-CHARACTERIZATION ,energy metabolism ,Brown adipose tissue ,Myocyte ,Cells, Cultured ,DOPAMINE D-1 ,Mice, Knockout ,BROWN ADIPOSE-TISSUE ,Middle Aged ,Muscle atrophy ,medicine.anatomical_structure ,adenosine ,SKELETAL-MUSCLE ,Obesitat ,medicine.symptom ,Life Sciences & Biomedicine ,STEM-CELLS ,Signal Transduction ,Adult ,medicine.medical_specialty ,Adolescent ,CROSS-TALK ,Mice, Transgenic ,Biology ,Receptor, Adenosine A2B ,Article ,sarcopenia ,Endocrinology & Metabolism ,Young Adult ,03 medical and health sciences ,Envelliment de la població ,Metabolic regulation ,Internal medicine ,adenosine receptor A2B ,medicine ,Animals ,Humans ,SARCOPENIC OBESITY ,INTERNATIONAL UNION ,Obesity ,Molecular Biology ,browning ,Science & Technology ,Skeletal muscle ,brown adipose tissue ,Cell Biology ,Adenosine Receptor A2b ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,FAT ,030217 neurology & neurosurgery ,Adenosine A2B receptor - Abstract
The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti-obesity potential. ispartof: Cell Metabolism vol:32 issue:1 pages:56+-56+ ispartof: location:United States status: Published online
- Published
- 2020
22. Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue
- Author
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Minna, Lahesmaa, Olof, Eriksson, Thorsten, Gnad, Vesa, Oikonen, Marco, Bucci, Jussi, Hirvonen, Kalle, Koskensalo, Jarmo, Teuho, Tarja, Niemi, Markku, Taittonen, Salla, Lahdenpohja, Mueez, U Din, Merja, Haaparanta-Solin, Alexander, Pfeifer, Kirsi A, Virtanen, and Pirjo, Nuutila
- Subjects
Adult ,Male ,Cold-Shock Response ,Thermogenesis ,Middle Aged ,Overweight ,Pyrrolidinones ,Rats ,Up-Regulation ,Rats, Sprague-Dawley ,Young Adult ,Adipose Tissue, Brown ,Receptor, Cannabinoid, CB1 ,Fluorodeoxyglucose F18 ,Positron-Emission Tomography ,Animals ,Humans ,Cells, Cultured - Abstract
Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [
- Published
- 2017
23. Increased cGMP promotes healthy expansion and browning of white adipose tissue
- Author
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Thorsten Gnad, Daniela Scholz, Michaela M. Mitschke, Peter Mayer, Bodo Haas, Katja Kruithoff, Linda S. Hoffmann, Antonia Sassmann, Alexander Pfeifer, and Ana Kilić
- Subjects
medicine.medical_specialty ,RHOA ,Adipose Tissue, White ,Adipokine ,Adipose tissue ,White adipose tissue ,Biochemistry ,Ion Channels ,Proinflammatory cytokine ,Mitochondrial Proteins ,Mice ,Adipose Tissue, Brown ,3T3-L1 Cells ,Internal medicine ,Adipocytes ,Cyclic GMP-Dependent Protein Kinases ,Genetics ,medicine ,Animals ,Obesity ,Protein kinase A ,Cyclic GMP ,Molecular Biology ,Uncoupling Protein 1 ,Adipogenesis ,biology ,Thermogenin ,Mitochondria ,Mice, Inbred C57BL ,Endocrinology ,biology.protein ,Signal Transduction ,Biotechnology - Abstract
With more than half a billion individuals affected worldwide, obesity has reached pandemic proportions. Development of "brown-like" or "brite" adipocytes within white adipose tissue (WAT) has potential antiobesity and insulin-sensitizing effects. We investigated the role of cyclic GMP (cGMP) signaling, focusing on cGMP-dependent protein kinase I (PKGI) in WAT. PKGI is expressed in murine WAT, primary adipocytes, and 3T3-L1. Treatment of adipocytes with cGMP resulted in increased adipogenesis, with a 54% increase in expression of peroxisome proliferator-activated receptor-γ. Lentiviral overexpression of PKGI further increased adipogenesis, whereas loss of PKGI significantly reduced adipogenic differentiation. In addition to adipogenic effects, PKGI had an antihypertrophic and anti-inflammatory effect via RhoA phosphorylation and reduction of proinflammatory adipokine expression. Moreover, PKGI induced a 4.3-fold increase in abundance of UCP-1 and the development of a brown-like thermogenic program in primary adipocytes. Notably, treatment of C57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 d caused 4.6-fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype ("browning") of WAT in vivo. Taken together, PKGI is a key regulator of cell size, adipokine secretion and browning of white fat depots and thus could be a valuable target in developing novel treatments for obesity.
- Published
- 2013
24. Ectodomain shedding of E-cadherin and c-Met is induced by Helicobacter pylori infection
- Author
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Shigeki Higashiyama, Carmen Wolke, Wiebke Schirrmeister, Thomas Wex, Thorsten Gnad, Michael Naumann, and Uwe Lendeckel
- Subjects
C-Met ,ADAM10 ,Population ,Glycine ,Gene Expression ,Hydroxamic Acids ,Transfection ,medicine.disease_cause ,Cell Line ,Helicobacter Infections ,Microbiology ,ADAM10 Protein ,chemistry.chemical_compound ,Stomach Neoplasms ,medicine ,Humans ,Protease Inhibitors ,RNA, Small Interfering ,education ,education.field_of_study ,Helicobacter pylori ,biology ,Cadherin ,Stomach ,Membrane Proteins ,Metalloendopeptidases ,Epithelial Cells ,Cell Biology ,Proto-Oncogene Proteins c-met ,Cadherins ,biology.organism_classification ,Peptide Fragments ,ADAM Proteins ,chemistry ,Ectodomain ,Immunology ,Disease Progression ,Hepatocyte growth factor ,Amyloid Precursor Protein Secretases ,Carcinogenesis ,medicine.drug - Abstract
Helicobacter pylori, a microaerophilic gram-negative bacterium, colonizes the human stomach. About 50% of the world's population is infected, and this infection is considered as the major risk factor for the development of gastric adenocarcinomas in 1% of infected subjects. Carcinogenesis is characterized by the process of epithelial-to-mesenchymal transition (EMT), in the course of which fully differentiated epithelial cells turn into depolarized and migratory cells. Concomitant disruption of adherence junctions (AJ) is facilitated by growth factors like hepatocyte growth factor 1 (HGF-1), but has been also shown to depend on ectodomain shedding of E-cadherin. The aim of this study was to investigate the impact of infection with H. pylori of NCI-N87 gastric epithelial cells on the shedding of E-cadherin and HGF-receptor c-Met. Our results show that infection with H. pylori provokes shedding of the surface proteins c-Met and E-cadherin. Evidence is provided that ADAM10 contributes to the shedding of c-Met and E-cadherin.
- Published
- 2009
25. Direct lentivirus injection for fast and efficient gene transfer into brown and beige adipose tissue
- Author
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Katarina Klepac, Linda S. Hoffmann, Aileen Balkow, Thorsten Gnad, Katrin Zimmermann, Anja Glöde, and Alexander Pfeifer
- Subjects
medicine.medical_specialty ,biology ,beige adipose tissue ,Transgene ,Adipose tissue ,brown adipose tissue ,White adipose tissue ,biology.organism_classification ,medicine.disease ,Fat pad ,medicine.anatomical_structure ,Endocrinology ,lentivirus ,In vivo ,Internal medicine ,Lentivirus ,Brown adipose tissue ,Protocol ,medicine ,General Earth and Planetary Sciences ,gene transfer ,Infiltration (medical) ,General Environmental Science - Abstract
Brown adipose tissue is a special type of fat contributing to energy expenditure in human newborns and adults. Moreover, subcutaneous white adipose tissue has a high capacity to adapt an energy-consuming, brown-like/beige phenotype. Here, we developed an easy to handle and fast to accomplish method to efficiently transfer genes into brown and beige fat pads in vivo. Lentiviral vectors are directly injected into the target fat pad of anaesthetized mice through a small incision using a modified, small needle connected to a microsyringe, which is well suited for infiltration of adipose tissues. Expression of the target gene can be detected in brown/beige fat one week after injection. The method can be applied within minutes to efficiently deliver transgenes into subcutaneous adipose tissues. Thus, this protocol allows for studying genes of interest in a timely manner in murine brown/beige fat and could potentially lead to new gene therapies for obesity. Brown adipose tissue is a special type of fat contributing to energy expenditure in human newborns and adults. Moreover, subcutaneous white adipose tissue has a high capacity to adapt an energy-consuming, brown-like/beige phenotype. Here, we developed an easy to handle and fast to accomplish method to efficiently transfer genes into brown and beige fat pads in vivo. Lentiviral vectors are directly injected into the target fat pad of anaesthetized mice through a small incision using a modified, small needle connected to a microsyringe, which is well suited for infiltration of adipose tissues. Expression of the target gene can be detected in brown/beige fat one week after injection. The method can be applied within minutes to efficiently deliver transgenes into subcutaneous adipose tissues. Thus, this protocol allows for studying genes of interest in a timely manner in murine brown/beige fat and could potentially lead to new gene therapies for obesity.
- Published
- 2016
26. Adenosine activates brown adipose tissue and recruits beige adipocytes via A(2A) receptors
- Author
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Matthias J. Betz, Thorsten Gnad, Laia Reverte-Salisa, Christa E. Müller, Samet Mutlu, Jürgen Schrader, Philipp Horn, Ivar von Kügelgen, Alexander Pfeifer, Ali El-Tayeb, Saskia Scheibler, Sven Enerbäck, Anja Glöde, Mathias Kranz, Linda S. Hoffmann, Winnie Deuther-Conrad, Peter Brust, Camilla Scheele, Gennady G. Yegutkin, Martin E. Lidell, and Ana Kilić
- Subjects
Male ,medicine.medical_specialty ,Adenosine ,Adenosine A2 Receptor Agonists ,Receptor, Adenosine A2A ,Adenosine A2A receptor ,Adipose tissue ,White adipose tissue ,Biology ,ta3111 ,Mice ,Adipose Tissue, Brown ,Internal medicine ,Cricetinae ,Brown adipose tissue ,Phenethylamines ,medicine ,Adipocytes ,Animals ,Humans ,Cells, Cultured ,Multidisciplinary ,Mesocricetus ,Purinergic receptor ,Purinergic signalling ,Adenosine receptor ,Research Highlight ,Diet ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,medicine.drug - Abstract
Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
- Published
- 2014
27. Helicobacter pylori-induced activation of β-catenin involves low density lipoprotein receptor-related protein 6 and Dishevelled
- Author
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Uwe Lendeckel, Maria Feoktistova, Michael Naumann, Thorsten Gnad, and Martin Leverkus
- Subjects
Cancer Research ,Beta-catenin ,Population ,Dishevelled Proteins ,Chronic gastritis ,Biology ,lcsh:RC254-282 ,Models, Biological ,Cell Line ,Helicobacter Infections ,Bacterial Proteins ,medicine ,Humans ,Phosphorylation ,education ,beta Catenin ,Adaptor Proteins, Signal Transducing ,chemistry.chemical_classification ,Cell Nucleus ,education.field_of_study ,Helicobacter pylori ,Research ,Wnt signaling pathway ,LRP6 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,biology.organism_classification ,Phosphoproteins ,Cell biology ,Dishevelled ,Oncology ,chemistry ,Gene Expression Regulation ,Receptors, LDL ,Catenin ,Gene Knockdown Techniques ,Low Density Lipoprotein Receptor-Related Protein-6 ,biology.protein ,Cancer research ,Molecular Medicine ,TCF Transcription Factors - Abstract
BackgroundThe human microbial pathogenHelicobacter pyloriresides in the stomach of about fifty percent of the world's population and represents a risk factor for chronic gastritis, peptic ulcers and, in rare cases, gastric cancer. Alterations of the Wnt/β-catenin signaling pathway have been described in almost every human cancer disease, due to the regulation of target genes being involved in cell cycle control, differentiation, cell migration or stem cell control. Our study aimed to elucidate the role of proximal Wnt signaling components low density lipoprotein receptor-related protein 6 (LRP6) and Dishevelled (Dvl) in the activation of β-catenin early after infection of gastric epithelial cells withH. pylori.ResultsInfection of gastric epithelial NCI-N87 cells withH. pyloriinduces rapid phosphorylation of the Wnt/β-catenin pathway co-receptor LRP6 independent of the cytotoxin-associated gene A (CagA) or vacuolating cytotoxin A (VacA). However, bacteria lacking a functional type 4 secretion system (T4SS) failed to induce LRP6 phosphorylation. Further, we identified proteins of the Dvl family, namely Dvl2 and Dvl3, which are involved in LRP6 phosphorylation.H. pylori-induced nuclear accumulation of β-catenin and its transcriptional activation, and expression of Wnt target genes are strongly reduced in stable knockdown cell lines deficient for LRP6, Dvl2 or Dvl3.ConclusionWe analysed theH. pylori-induced activation of Wnt-signaling factors and demonstrate for the first time that the canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of β-catenin.
- Published
- 2010
28. Helicobacter pylori promotes eukaryotic protein translation by activating phosphatidylinositol 3 kinase/mTOR
- Author
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Thorsten Gnad, Michael Vieth, Przemyslaw Bozko, Olga Sokolova, and Michael Naumann
- Subjects
Adult ,Elongation Factor 2 Kinase ,Blotting, Western ,Cell Cycle Proteins ,Biology ,Biochemistry ,mTORC2 ,Helicobacter Infections ,Receptor, IGF Type 1 ,Young Adult ,S6 ribosomal protein ,Cell Line, Tumor ,Humans ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Adaptor Proteins, Signal Transducing ,Aged ,Aged, 80 and over ,Helicobacter pylori ,Kinase ,Ribosomal Protein S6 Kinases ,TOR Serine-Threonine Kinases ,EIF4E ,RPTOR ,Cell Biology ,Middle Aged ,Phosphoproteins ,Cell biology ,Enzyme Activation ,Eukaryotic Initiation Factor-4E ,Protein Biosynthesis ,Host-Pathogen Interactions ,mTOR ,eIF4 ,Phosphatidylinositol 3-Kinase ,Signal transduction ,Protein synthesis ,Proto-Oncogene Proteins c-akt ,H. pylori ,Signal Transduction - Abstract
The innate immune response elicited by Helicobacter pylori in the human gastric mucosa involves a range of cellular signalling pathways, including those implicated in metabolism regulation. In this study, we analysed H. pylori-induced PI3K/Akt/mTOR signalling, which regulates glycolysis and protein synthesis and associates thereby with cellular energy- and nutrients-consuming processes such as growth and proliferation. The immunohistochemical analysis demonstrated that Akt kinase phosphorylation is abundant in gastric biopsies obtained from gastritis, gastric adenoma and adenocarcinoma patients. Infection with H. pylori led to the phosphorylation of Akt effectors mTOR and S6 in a type 4 secretion system (T4SS)-independent manner in AGS cells. We observed that the activation of these molecules was dependent on PI3K and the Src family tyrosine kinases. Furthermore, H. pylori induced the phosphorylation of 4E-BP1 and eIF4E and suppressed the phosphorylation of eEF2, which are important regulators of protein synthesis. Inhibition of PI3K and Akt kinase prevented the phosphorylation of 4E-BP1, suggesting that PI3K signalling is involved in the regulation of translation initiation during H. pylori infection. Metabolic labelling showed that infected cells had higher rates of [35S]methionine/cysteine incorporation, and this effect could be prevented using LY294002, an PI3K inhibitor. Thus, H. pylori activates PI3K/Akt signalling, mTOR, eIFs and protein translation, which might impact H. pylori-related gastric pathophysiology.
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