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2. Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health

Author

Lecoutre, Simon, Maqdasy, Salwan, Rizo-Roca, David, Renzi, Gianluca, Vlassakev, Ivan, Alaeddine, Lynn M., Higos, Romane, Jalkanen, Jutta, Zhong, Jiawei, Zareifi, Danae S., Frendo-Cumbo, Scott, Massier, Lucas, Hodek, Ondrej, Juvany, Marta, Moritz, Thomas, de Castro Barbosa, Thais, Omar-Hmeadi, Muhmmad, López-Yus, Marta, Merabtene, Fatiha, Abatan, Jimon Boniface, Marcelin, Geneviève, El Hachem, Elie-Julien, Rouault, Christine, Bergo, Martin O., Petrus, Paul, Zierath, Juleen R., Clément, Karine, Krook, Anna, Mejhert, Niklas, and Rydén, Mikael

Published
2024
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3. Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity

Author

Jiang, Shan, Yuan, Taolin, Rosenberger, Florian A., Mourier, Arnaud, Dragano, Nathalia R. V., Kremer, Laura S., Rubalcava-Gracia, Diana, Hansen, Fynn M., Borg, Melissa, Mennuni, Mara, Filograna, Roberta, Alsina, David, Misic, Jelena, Koolmeister, Camilla, Papadea, Polyxeni, de Angelis, Martin Hrabe, Ren, Lipeng, Andersson, Olov, Unger, Anke, Bergbrede, Tim, Di Lucrezia, Raffaella, Wibom, Rolf, Zierath, Juleen R., Krook, Anna, Giavalisco, Patrick, Mann, Matthias, and Larsson, Nils-Göran

Published
2024
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4. Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism

Author

Nomura, Kazuhiro, Kinoshita, Shinichi, Mizusaki, Nao, Senga, Yoko, Sasaki, Tsutomu, Kitamura, Tadahiro, Sakaue, Hiroshi, Emi, Aki, Hosooka, Tetsuya, Matsuo, Masahiro, Okamura, Hitoshi, Amo, Taku, Wolf, Alexander M., Kamimura, Naomi, Ohta, Shigeo, Itoh, Tomoo, Hayashi, Yoshitake, Kiyonari, Hiroshi, Krook, Anna, Zierath, Juleen R., Kasuga, Masato, and Ogawa, Wataru

Published
2024
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7. Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M

Author

Dollet, Lucile, Lundell, Leonidas S., Chibalin, Alexander V., Pendergrast, Logan A., Pillon, Nicolas J., Lansbury, Elizabeth L., Elmastas, Merve, Frendo-Cumbo, Scott, Jalkanen, Jutta, de Castro Barbosa, Thais, Cervone, Daniel T., Caidahl, Kenneth, Dmytriyeva, Oksana, Deshmukh, Atul S., Barrès, Romain, Rydén, Mikael, Wallberg-Henriksson, Harriet, Zierath, Juleen R., and Krook, Anna

Published
2024
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8. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R., Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C., Rivera, Natalia V., Robiou-du-Pont, Sebastien, Schraut, Katharina E., Schulz, Christina-Alexandra, Stringham, Heather M., Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J., Vanmunster, Mathias, van Rooij, Frank J. A., van Vliet-Ostaptchouk, Jana V., Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N., Baumeister, Sebastian E., Beilby, John, Blangero, John, Boomsma, Dorret I., Brage, Soren, Braund, Peter S., Brody, Jennifer A., Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W., Collins, Francis S., Cupples, L. Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D., Fernandez-Rhodes, Lindsay, Fohner, Alison E., Franco, Oscar H., Galesloot, Tessel E., Gordon, Scott D., Grarup, Niels, Hartman, Catharina A., Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K., Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P., Kuusisto, Johanna, Launer, Lenore J., Li, Aihua, Linneberg, Allan, Luan, Jian’an, Vidal, Pedro Marques, Medland, Sarah E., Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P., Nolte, Ilja M., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Power, Christine, Raitakari, Olli T., Reedik, Mägi, Reiner, Alex P., Ridker, Paul M., Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A., Scott, Laura J., Scott, Robert A., Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V., Smith, Jennifer A., Sonestedt, Emily, Strøm, Marin, Tai, E. Shyong, Teo, Koon K., Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G., Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L., Yuan, Jian Min, Zillikens, M. Carola, Zonderman, Alan B., Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C., Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I., Smith, George Davey, de Geus, Eco J. C., Deldicque, Louise, Dörr, Marcus, Evans, Michele K., Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Jr, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L., Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W. Craig, Kardia, Sharon L. R., Kiemeney, Lambertus A., Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Magnusson, Patrik K. E., Martin, Nicholas G., Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E., Ohlsson, Claes, Oldehinkel, Albertine J., Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W. J. H., Pers, Tune H., Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N., Samani, Nilesh J., Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Timpson, Nicholas J., van Dam, Rob M., van der Velde, Nathalie, van Duijn, Cornelia M., Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J., Weir, David R., Wichmann, Heinz-Erich, Wilson, James F., Hevener, Andrea L., Krook, Anna, Zierath, Juleen R., Thomis, Martine A. I., Loos, Ruth J. F., and Hoed, Marcel den

Published
2022
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12. Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.

Author

Rizo-Roca, David, Guimarães, Dimitrius Santiago P. S. F., Pendergrast, Logan A., Di Leo, Nicolas, Chibalin, Alexander V., Maqdasy, Salwan, Rydén, Mikael, Näslund, Erik, Zierath, Juleen R., and Krook, Anna

Subjects
TYPE 2 diabetes, CREATINE kinase, OXIDATION of glucose, INSULIN resistance, HIGH-fat diet
Abstract

Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced. These alterations were coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C57BL/6 mice fed a high-fat diet, neither supplementation with creatine for 2 weeks nor treatment with the creatine analog β-GPA for 1 week induced changes in glucose tolerance, suggesting that increased circulating creatine was associated with insulin resistance rather than causing it. In C2C12 myotubes, silencing Ckmt2 using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet–fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of Ckmt2 improved mitochondrial function, we explored whether exercise regulates CKMT2 expression. Analysis of public data revealed that CKMT2 content was up-regulated by exercise training in both humans and mice. We reveal a previously underappreciated role of CKMT2 in mitochondrial homeostasis beyond its function for creatine phosphorylation, independent of insulin action. Collectively, our data provide functional evidence for how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes. Editor's summary: Increased plasma creatine is associated with type 2 diabetes, but causation has not been established. Rizo-Roca et al. show that men with type 2 diabetes had increased plasma creatine and decreased muscle phosphocreatine, which was associated with poor glucose handling. In myotubes in vitro, silencing the mitochondria-associated sarcomeric mitochondrial creatine kinase 2 (Ckmt2) gene resulted in impaired mitochondrial functions. In mice fed a high-fat diet, creatine supplementation had no effect on glucose handling, but overexpression of Ckmt2 in muscle improved mitochondrial functions. Data from humans and mice showed that exercise increased CKMT2 and metrics of mitochondrial functions. These results suggest that creatine changes are a consequence rather than a cause of insulin resistance in type 2 diabetes. —Brandon Berry [ABSTRACT FROM AUTHOR]

Published
2024
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14. miR-29a-3p, a new myokine orchestrating resistance exercise via coordinated metabolic responses

Author

Pinto-Hernandez, Paola, primary, Fernandez-Sanjurjo, Manuel, additional, Paget, Daan, additional, Caravia, Xurde M, additional, Roiz-Valle, David, additional, Castilla-Silgado, Juan, additional, Diez-Robles, Sergio, additional, Coto-Vilcapoma, Almudena, additional, Gama, Pau, additional, Garcia-Roves, Pablo M, additional, Lopez-Otin, Carlos, additional, Zierath, Juleen R, additional, Krook, Anna, additional, Fernandez-Garcia, Benjamin, additional, Tomas-Zapico, Cristina, additional, and Iglesias-Gutierrez, Eduardo, additional

Published
2024
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18. Exercise-induced crosstalk between immune cells and adipocytes in humans:Role of oncostatin-M

Author

Dollet, Lucile, Lundell, Leonidas S., Chibalin, Alexander V., Pendergrast, Logan A., Pillon, Nicolas J., Lansbury, Elizabeth L., Elmastas, Merve, Frendo-Cumbo, Scott, Jalkanen, Jutta, de Castro Barbosa, Thais, Cervone, Daniel T., Caidahl, Kenneth, Dmytriyeva, Oksana, Deshmukh, Atul S., Barrès, Romain, Rydén, Mikael, Wallberg-Henriksson, Harriet, Zierath, Juleen R., Krook, Anna, Dollet, Lucile, Lundell, Leonidas S., Chibalin, Alexander V., Pendergrast, Logan A., Pillon, Nicolas J., Lansbury, Elizabeth L., Elmastas, Merve, Frendo-Cumbo, Scott, Jalkanen, Jutta, de Castro Barbosa, Thais, Cervone, Daniel T., Caidahl, Kenneth, Dmytriyeva, Oksana, Deshmukh, Atul S., Barrès, Romain, Rydén, Mikael, Wallberg-Henriksson, Harriet, Zierath, Juleen R., and Krook, Anna

Abstract

The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise. In cultured human adipocytes, oncostatin-M enhances MAPK signaling and regulates lipolysis. Oncostatin-M expression arises predominantly from adipose tissue immune cell fractions, while the corresponding receptors are expressed in adipocytes. Oncostatin-M expression increases in cultured human Thp1 macrophages following exercise-like stimuli. Our results suggest that immune cells, via secreted factors such as oncostatin-M, mediate a crosstalk between skeletal muscle and adipose tissue during exercise to regulate adipocyte metabolism and adaptation.

Published
2024

21. Glutamine Links Obesity to Inflammation in Human White Adipose Tissue

Author

Petrus, Paul, Lecoutre, Simon, Dollet, Lucile, Wiel, Clotilde, Sulen, André, Gao, Hui, Tavira, Beatriz, Laurencikiene, Jurga, Rooyackers, Olav, Checa, Antonio, Douagi, Iyadh, Wheelock, Craig E., Arner, Peter, McCarthy, Mark, Bergo, Martin O., Edgar, Laurienne, Choudhury, Robin P., Aouadi, Myriam, Krook, Anna, and Rydén, Mikael

Published
2020
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22. Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M

Author

Dollet, Lucile, primary, Lundell, Leonidas S., additional, Chibalin, Alexander V., additional, Pendergrast, Logan A., additional, Pillon, Nicolas J., additional, Lansbury, Elizabeth L., additional, Elmastas, Merve, additional, Frendo-Cumbo, Scott, additional, Jalkanen, Jutta, additional, de Castro Barbosa, Thais, additional, Cervone, Daniel T., additional, Caidahl, Kenneth, additional, Dmytriyeva, Oksana, additional, Deshmukh, Atul S., additional, Barrès, Romain, additional, Rydén, Mikael, additional, Wallberg-Henriksson, Harriet, additional, Zierath, Juleen R., additional, and Krook, Anna, additional

Published
2023
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33. Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6

Author

Guimarães, Dimitrius Santiago P.S.F., primary, Barrios, Ninon M.F., additional, de Oliveira, André Gustavo, additional, Rizo-Roca, David, additional, Jollet, Maxence, additional, Smith, Jonathon A.B., additional, Araujo, Thiago R., additional, da Cruz, Marcos Vinicius, additional, Junior, Emilio Marconato, additional, Hirabara, Sandro M., additional, Vieira, André S., additional, Krook, Anna, additional, Zierath, Juleen R., additional, and Silveira, Leonardo R., additional

Published
2023
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34. Time of day determines postexercise metabolism in mouse adipose tissue

Author

Pendergrast, Logan A., Lundell, Leonidas S., Ehrlich, Amy M., Ashcroft, Stephen P., Schönke, Milena, Basse, Astrid L., Krook, Anna, Treebak, Jonas T., Dollet, Lucile, Zierath, Juleen R., Pendergrast, Logan A., Lundell, Leonidas S., Ehrlich, Amy M., Ashcroft, Stephen P., Schönke, Milena, Basse, Astrid L., Krook, Anna, Treebak, Jonas T., Dollet, Lucile, and Zierath, Juleen R.

Abstract

The circadian clock is a cell-autonomous transcription–translation feedback mechanism that anticipates and adapts physiology and behavior to different phases of the day. A variety of factors including hormones, temperature, food-intake, and exercise can act on tissue-specific peripheral clocks to alter the expression of genes that influence metabolism, all in a time-of-day dependent manner. The aim of this study was to elucidate the effects of exercise timing on adipose tissue metabolism. We performed RNA sequencing on inguinal adipose tissue of mice immediately following maximal exercise or sham treatment at the early rest or early active phase. Only during the early active phase did exercise elicit an immediate increase in serum nonesterified fatty acids. Furthermore, early active phase exercise increased expression of markers of thermogenesis and mitochondrial proliferation in inguinal adipose tissue. In vitro, synchronized 3T3-L1 adipocytes showed a timing-dependent difference in Adrb2 expression, as well as a greater lipolytic activity. Thus, the response of adipose tissue to exercise is time-of-day sensitive and may be partly driven by the circadian clock. To determine the influence of feeding state on the time-of-day response to exercise, we replicated the experiment in 10-h-fasted early rest phase mice to mimic the early active phase metabolic status. A 10-h fast led to a similar lipolytic response as observed after active phase exercise but did not replicate the transcriptomic response, suggesting that the observed changes in gene expression are not driven by feeding status. In conclusion, acute exercise elicits timing-specific effects on adipose tissue to maintain metabolic homeostasis.

Published
2023

35. Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle

Author

Abdelmoez, Ahmed M., Dmytriyeva, Oksana, Zurke, Yasemin Xiomara, Trauelsen, Mette, Marica, Alesandra A., Savikj, Mladen, Smith, Jonathon A.B., Monaco, Claudia, Schwartz, Thue W., Krook, Anna, Pillon, Nicolas J., Abdelmoez, Ahmed M., Dmytriyeva, Oksana, Zurke, Yasemin Xiomara, Trauelsen, Mette, Marica, Alesandra A., Savikj, Mladen, Smith, Jonathon A.B., Monaco, Claudia, Schwartz, Thue W., Krook, Anna, and Pillon, Nicolas J.

Abstract

Succinate is released by skeletal muscle during exercise and activates SUCNR1/GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that SUCNR1 mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, SUCNR1 mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, SUCNR1 mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of SUCNR1 mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle.NEW & NOTEWORTHY Macrophages but not skeletal muscle cells respond to extracellular succinate via SUCNR1/GPR91.

Published
2023

43. Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers

Author

Pillon, Nicolas J, primary, Sardón Puig, Laura, additional, Altıntaş, Ali, additional, Kamble, Prasad G, additional, Casaní-Galdón, Salvador, additional, Gabriel, Brendan M, additional, Barrès, Romain, additional, Conesa, Ana, additional, Chibalin, Alexander V, additional, Näslund, Erik, additional, Krook, Anna, additional, and Zierath, Juleen R, additional

Published
2022
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44. Distinctive exercise-induced inflammatory response and exerkine induction in skeletal muscle of people with type 2 diabetes

Author

Pillon, Nicolas J., primary, Smith, Jonathon A. B., additional, Alm, Petter S., additional, Chibalin, Alexander V., additional, Alhusen, Julia, additional, Arner, Erik, additional, Carninci, Piero, additional, Fritz, Tomas, additional, Otten, Julia, additional, Olsson, Tommy, additional, van Doorslaer de ten Ryen, Sophie, additional, Deldicque, Louise, additional, Caidahl, Kenneth, additional, Wallberg-Henriksson, Harriet, additional, Krook, Anna, additional, and Zierath, Juleen R., additional

Published
2022
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47. Distinctive exercise-induced inflammatory response and exerkine induction in skeletal muscle of people with type 2 diabetes

Author

Pillon, Nicolas J., Smith, Jonathon A B, Alm, Petter S., Chibalin, Alexander V., Alhusen, Julia, Arner, Erik, Carninci, Piero, Fritz, Tomas, Otten, Julia, Olsson, Tommy, van Doorslaer de Ten Ryen, Sophie, Deldicque, Louise, Caidahl, Kenneth, Wallberg-Henriksson, Harriet, Krook, Anna, Zierath, Juleen R., Pillon, Nicolas J., Smith, Jonathon A B, Alm, Petter S., Chibalin, Alexander V., Alhusen, Julia, Arner, Erik, Carninci, Piero, Fritz, Tomas, Otten, Julia, Olsson, Tommy, van Doorslaer de Ten Ryen, Sophie, Deldicque, Louise, Caidahl, Kenneth, Wallberg-Henriksson, Harriet, Krook, Anna, and Zierath, Juleen R.

Abstract

Mechanistic insights into the molecular events by which exercise enhances the skeletal muscle phenotype are lacking, particularly in the context of type 2 diabetes. Here, we unravel a fundamental role for exercise-responsive cytokines (exerkines) on skeletal muscle development and growth in individuals with normal glucose tolerance or type 2 diabetes. Acute exercise triggered an inflammatory response in skeletal muscle, concomitant with an infiltration of immune cells. These exercise effects were potentiated in type 2 diabetes. In response to contraction or hypoxia, cytokines were mainly produced by endothelial cells and macrophages. The chemokine CXCL12 was induced by hypoxia in endothelial cells, as well as by conditioned medium from contracted myotubes in macrophages. We found that CXCL12 was associated with skeletal muscle remodeling after exercise and differentiation of cultured muscle. Collectively, acute aerobic exercise mounts a noncanonical inflammatory response, with an atypical production of exerkines, which is potentiated in type 2 diabetes.

Published
2022
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48. Distinctive exercise-induced inflammatory response and exerkine induction in skeletal muscle of people with type 2 diabetes.

Author

UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Pillon, Nicolas J, Smith, Jonathon A B, Alm, Petter S, Chibalin, Alexander V, Alhusen, Julia, Arner, Erik, Carninci, Piero, Fritz, Tomas, Otten, Julia, Olsson, Tommy, van Doorslaer de Ten Ryen, Sophie, Deldicque, Louise, Caidahl, Kenneth, Wallberg-Henriksson, Harriet, Krook, Anna, Zierath, Juleen R, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Pillon, Nicolas J, Smith, Jonathon A B, Alm, Petter S, Chibalin, Alexander V, Alhusen, Julia, Arner, Erik, Carninci, Piero, Fritz, Tomas, Otten, Julia, Olsson, Tommy, van Doorslaer de Ten Ryen, Sophie, Deldicque, Louise, Caidahl, Kenneth, Wallberg-Henriksson, Harriet, Krook, Anna, and Zierath, Juleen R

Abstract

Mechanistic insights into the molecular events by which exercise enhances the skeletal muscle phenotype are lacking, particularly in the context of type 2 diabetes. Here, we unravel a fundamental role for exercise-responsive cytokines () on skeletal muscle development and growth in individuals with normal glucose tolerance or type 2 diabetes. Acute exercise triggered an inflammatory response in skeletal muscle, concomitant with an infiltration of immune cells. These exercise effects were potentiated in type 2 diabetes. In response to contraction or hypoxia, cytokines were mainly produced by endothelial cells and macrophages. The chemokine CXCL12 was induced by hypoxia in endothelial cells, as well as by conditioned medium from contracted myotubes in macrophages. We found that CXCL12 was associated with skeletal muscle remodeling after exercise and differentiation of cultured muscle. Collectively, acute aerobic exercise mounts a noncanonical inflammatory response, with an atypical production of exerkines, which is potentiated in type 2 diabetes.

Published
2022

49. Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers

Author

Pillon, Nicolas J., Puig, Laura Sardón, Altıntaş, Ali, Kamble, Prasad G, Casaní-Galdón, Salvador, Gabriel, Brendan M, Barrès, Romain, Conesa, Ana, Chibalin, Alexander V, Näslund, Erik, Krook, Anna, Zierath, Juleen R, Pillon, Nicolas J., Puig, Laura Sardón, Altıntaş, Ali, Kamble, Prasad G, Casaní-Galdón, Salvador, Gabriel, Brendan M, Barrès, Romain, Conesa, Ana, Chibalin, Alexander V, Näslund, Erik, Krook, Anna, and Zierath, Juleen R

Published
2022

50. Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes

Author

Dollet, Lucile, Kuefner, Michael, Caria, Elena, Rizo-Roca, David, Pendergrast, Logan, Abdelmoez, Ahmed M, Karlsson, Håkan Kr, Dalbram, Emilie, Treebak, Jonas, Harada, Jun, Näslund, Erik, Rydén, Mikael, Zierath, Juleen R, Pillon, Nicolas J, Krook, Anna, Dollet, Lucile, Kuefner, Michael, Caria, Elena, Rizo-Roca, David, Pendergrast, Logan, Abdelmoez, Ahmed M, Karlsson, Håkan Kr, Dalbram, Emilie, Treebak, Jonas, Harada, Jun, Näslund, Erik, Rydén, Mikael, Zierath, Juleen R, Pillon, Nicolas J, and Krook, Anna

Abstract

Dysregulation of skeletal muscle metabolism influences whole body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes-associated alterations in the plasma metabolome directly contributes to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that was inversely correlating with body mass index (BMI) and HOMA-IR index in people with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulates the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase of glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.

Published
2022

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