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1. Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion

Author

Veprik, Anna, Denwood, Geoffrey, Liu, Dong, Bany Bakar, Rula, Morfin, Valentin, McHugh, Kara, Tebeka, Nchimunya N, Vetterli, Laurène, Yonova-Doing, Ekaterina, Gribble, Fiona, Reimann, Frank, Hoehn, Kyle L, Hemsley, Piers A, Ahnfelt-Rønne, Jonas, Rorsman, Patrik, Zhang, Quan, De Wet, Heidi, Cantley, James, Veprik, Anna [0000-0002-3904-7151], Bany Bakar, Rula [0000-0002-5643-0195], McHugh, Kara [0000-0002-2629-986X], Tebeka, Nchimunya N [0000-0003-3916-6107], Gribble, Fiona [0000-0002-4232-2898], Reimann, Frank [0000-0001-9399-6377], Hoehn, Kyle L [0000-0002-0214-3238], Hemsley, Piers A [0000-0003-2950-0634], Rorsman, Patrik [0000-0001-7578-0767], Zhang, Quan [0000-0002-3626-4855], de Wet, Heidi [0000-0002-9871-6909], Cantley, James [0000-0003-2509-1271], and Apollo - University of Cambridge Repository

Subjects
Mice, endocrine system, Glucose, Acetyl Coenzyme A, Glucagon-Secreting Cells, Insulin-Secreting Cells, Animals, Medicine (miscellaneous), Glucagon, General Agricultural and Biological Sciences, hormones, hormone substitutes, and hormone antagonists, General Biochemistry, Genetics and Molecular Biology, Acetyl-CoA Carboxylase
Abstract

Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.

Published
2022
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2. Additional file 1 of Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15

Author

Zunica, Elizabeth R. M., Axelrod, Christopher L., Cho, Eunhan, Spielmann, Guillaume, Davuluri, Gangarao, Alexopoulos, Stephanie J., Beretta, Martina, Hoehn, Kyle L., Dantas, Wagner S., Stadler, Krisztian, King, William T., Pergola, Kathryn, Irving, Brian A., Langohr, Ingeborg M., Yang, Shengping, Hoppel, Charles L., Gilmore, L. Anne, and Kirwan, John P.

Abstract

Additional file 1: Table S1. Related to Figure S2. List of gene symbols, adjusted p-values, and log2 fold changes after 16-hr treatment with BAM15. Figure S1. Related to Figure 1. BAM15-mediated mitochondrial uncoupling reduces cell viability, proliferation, and migration in human TNBC and murine luminal B breast cancer cells. Figure S2. Related to Figure 2. BAM15 reduces the expression of genes required for cellular proliferation and energy production in MDA-MB-231 cells. Figure S3. Related to Figure 3. BAM15 reduces OXPHOS and glycolytic capacity via ΔΨm destabilization in MDA-MB-231 and EO771 cells. Figure S4. Related to Figure 4. BAM15 suppresses tumor growth in C57BL/6J mice.

Published
2021
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3. Mitochondrial respiratory states and rates

Author

Gnaiger, Erich, Aasander Frostner, Eleonor, Abdul Karim, Norwahidah, Abumrad, Nada A, Acuna-Castroviejo, Dario, Adiele, Reginald C, Ahn, Bumsoo, Ali, Sameh S, Alton, Lesley, Alves, Marco G, Amati, Francesca, Amoedo, Nivea Dias, Andreadou, Ioanna, Arago, Marc, Aral, Cenk, Arandarcikaite, Odeta, Armand, Anne-Sophie, Arnould, Thierry, Avram, Vlad Florian, Bailey, Damian M, Bajpeyi, Sudip, Bajzikova, Martina, Bakker, Barbara M, Barlow, Jonathan, Bastos Sant'Anna Silva, Ana Carolina, Batterson, Philip, Battino, Maurizio, Bazil, Jason, Beard, Daniel A, Bednarczyk, Piotr, Bello, Fiona, Ben-Shachar, Dorit, Bergdahl, Andreas, Berge, Rolf K, Bergmeister, Lisa, Bernardi, Paolo, Berridge, Michael V, Bettinazzi, Stefano, Bishop, David, Blier, Pierre U, Blindheim, Dan Filip, Boardman, Neoma T, Boetker, Hans Erik, Borchard, Sabine, Boros, Mihaly, Borsheim, Elisabet, Borutaite, Vilma, Botella, Javier, Bouillaud, Frederic, Bouitbir, Jamal, Boushel, Robert C, Bovard, Josh, Breton, Sophie, Brown, David A, Brown, Guy C, Brown, Robert A, Brozinick, Joseph T, Buettner, Garry R, Burtscher, Johannes, Calabria, Elisa, Calbet, Jose A, Calzia, Enrico, Cannon, Daniel T, Cano Sanchez, Maria, Canto Alvarez, Carlos, Cardoso, Luiza Helena Daltro, Carvalho, Eugenia, Casado Pinna, Marta, Cassar, Samantha, Cassina, Adriana M, Castelo, Maria P, Gonzalez-Franquesa, A, Cavalcanti-de-Albuquerque, Joao Paulo, Cervinkova, Zuzana, Chabi, Beatrice, Chakrabarti, Lisa, Chakrabarti, Sasanka, Chaurasia, Bhagirath, Chen, Qi, Chicco, Adam J, Chinopoulos, Christos, Chowdhury, Subir K, Cizmarova, Beata, Clementi, Emilio, Coen, Paul M, Cohen, Bruce H, Coker, Robert H, Collin, Anne, Crisostomo, Luis, Dahdah, Norma, Dalgaard, Louise T, Dambrova, Maija, Danhelovska, Tereza, Darveau, Charles A, Das, Anibh M, Dash, Ranjan K, Davidova, Eliska, Davis, Michael S, De Goede, Paul, De Palma, Clara, Dembinska-Kiec, Aldona, Detraux, Damien, Devaux, Yvan, Di Marcello, Marco, Dias, Tania R, Distefano, Giovanna, Doermann, Niklas, Doerrier, Carolina, Dong, Lan-Feng, Donnelly, Chris, Drahota, Zdenek, Duarte, Filipe Valente, Dubouchaud, Herve, Duchen, Michael R, Dumas, Jean-Francois, Durham, William J, Dymkowska, Dorota, Dyrstad, Sissel E, Dyson, Alex, Dzialowski, Edward M, Eaton, Simon, Ehinger, Johannes, Elmer, Eskil, Endlicher, Rene, Engin, Ayse B, Escames, Germaine, Ezrova, Zuzana, Falk, Marni Joy, Fell, David A, Ferdinandy, Peter, Ferko, Miroslav, Ferreira, Julio Cesar Batista, Ferreira, Rita, Ferri, Alessandra, Fessel, Joshua P, Filipovska, Aleksandra, Fisar, Zdenek, Fischer, Christine, Fischer, Michael, Fisher, Gordon, Fisher, Joshua J, Ford, Ellen, Fornaro, Mara, Galina, Antonio, Galkin, Alexander, Gallee, Leon, Galli, Gina L, Gama Perez, Pau, Gan, Zhenji, Ganetzky, Rebecca, Garcia-Rivas, Gerardo, Garcia-Roves, Pablo Miguel, Garcia-Souza, Luiz Felipe, Garipi, Enis, Garlid, Keith D, Garrabou, Gloria, Garten, Antje, Gastaldelli, Amalia, Gayen, Jiaur, Genders, Amanda J, Genova, Maria Luisa, Giovarelli, Matteo, Goncalo Teixeira da Silva, Rui, Goncalves, Debora Farina, Gonzalez-Armenta, Jenny L, Gonzalez-Freire, Marta, Gonzalo, Hugo, Goodpaster, Bret H, Gorr, Thomas A, Gourlay, Campbell W, Granata, Cesare, Grefte, Sander, Guarch, Meritxell Espino, Gueguen, Naig, Gumeni, Sentiljana, Haas, Clarissa B, Haavik, Jan, Haendeler, Judith, Haider, Markus, Hamann, Andrea, Han, Jin, Han, Woo Hyun, Hancock, Chad R, Hand, Steven C, Handl, Jiri, Hargreaves, Ian P, Harper, Mary Ellen, Harrison, David K, Hassan, Hazirah, Hausenloy, Derek J, Heales, Simon JR, Heiestad, Christina, Hellgren, Kim T, Hepple, Russell T, Hernansanz-Agustin, Pablo, Hewakapuge, Sudinna, Hickey, Anthony J, Ho, Dieu Hien, Hoehn, Kyle L, Hoel, Frederik, Holland, Olivia J, Holloway, Graham P, Hoppel, Charles L, Hoppel, Florian, Houstek, Josef, Huete-Ortega, Maria, Hyrossova, Petra, Iglesias-Gonzalez, Javier, Irving, Brian A, Isola, Raffaella, Iyer, Shilpa, Jackson, Christophe B, Jadiya, Pooja, Jana, Prado Fabian, Jang, David H, Jang, Young C, Janowska, Joanna, Jansen, Kirsten, Jansen-Duerr, Pidder, Jansone, Baiba, Jarmuszkiewicz, Wieslawa, Jaskiewicz, Anna, Jedlicka, Jan, Jespersen, Nichlas R, Jha, Rajan K, Jurczak, Michael J, Jurk, Diana, Kaambre, Tuuli, Kaczor, Jan J, Kainulainen, Heikki, Kampa, Rafal Pawel, Kandel, Sunil M, Kane, Daniel A, Kapferer, Werner, Kappler, Lisa, Karabatsiakis, Alexander, Karkucinska-Wieckowska, Agnieszka, Kaur, Sarbjot, Keijer, Jaap, Keller, Markus A, Keppner, Gloria, Khamoui, Andy V, Kidere, Dita, Kilbaugh, Todd, Kim, Hyoung Kyu, Kim, Julian KS, Klepinin, Aleksandr, Klepinina, Lyudmila, Klingenspor, Martin, Klocker, Helmut, Komlódi, Timea, Koopman, Werner JH, Kopitar-Jerala, Natasa, Kowaltowski, Alicia J, Kozlov, Andrey V, Krajcova, Adela, Krako Jakovljevic, Nina, Kristal, Bruce S, Krycer, Jamer R, Kuang, Jujiao, Kucera, Otto, Kuka, Janis, Kwak, Hyo Bum, Kwast, Kurt, Laasmaa, Martin, Labieniec-Watala, Magdalena, Lai, Nicola, Land, John M, Lane, Nick, Laner, Verena, Lanza, Ian R, Larsen, Terje S, Lavery, Gareth G, Lazou, Antigone, Lee, Hong Kyu, Leeuwenburgh, Christiaan, Lehti, Maarit, Lemieux, Helene, Lenaz, Giorgio, Lerfall, Jorgen, Li, Pingan A, Li Puma, Lance, Liepins, Edgars, Lionett, Sofie, Liu, Jiankang, Lopez, Luis C, Lucchinetti, Eliana, Ma, Tao, Macedo, Maria P, Maciej, Sarah, MacMillan-Crow, Lee Ann, Majtnerova, Pavlina, Makarova, Elina, Makrecka-Kuka, Marina, Malik, Afshan N, Markova, Michaela, Martin, Daniel S, Martins, Ana Dias, Martins, Joao D, Maseko, Tumisang Edward, Maull, Felicia, Mazat, Jean Pierre, McKenna, Helen T, McKenzie, Matthew, Menze, Michael A, Merz, Tamara, Meszaros, Andras T, Methner, Axel, Michalak, Slawomir, Moellering, Douglas R, Moisoi, Nicoleta, Molina, Anthony JA, Montaigne, David, Moore, Anthony L, Moreau, Kerrie, Moreira, Bruno P, Moreno-Sanchez, Rafael, Mracek, Tomas, Muccini, Anna Maria, Muntane, Jordi, Muntean, Danina M, Murray, Andrew J, Musiol, Eva, Nabben, Miranda, Nair, K Sreekumaran, Nehlin, Jan O, Nemec, Michal, Neufer, P Darrell, Neuzil, Jiri, Neviere, Remi, Newsom, Sean A., Nozickova, Katerina, O'Brien, Katie A, O'Gorman, Donal, Olgar, Yusuf, Oliveira, Ben, Oliveira, Marcus F, Oliveira, Marcos Tulio, Oliveira, Pedro F, Oliveira, Paulo J, Orynbayeva, Zulfiya, Osiewacz, Heinz D, Pak, Youngmi K, Pallotta, Maria L, Palmeira, Carlos M, Parajuli, Nirmala, Passos, Joao F, Passrugger, Manuela, Patel, Hemal H, Pavlova, Nadia, Pecina, Petr, Pedersen, Tina M, Pereira da Silva Grilo da Silva, Filomena, Perez Valencia, Juan A, Perks, Kara L, Pesta, Dominik, Petit, Patrice X, Pettersen, Ina Katrine Nitschke, Pichaud, Nicolas, Pichler, Irene, Piel, Sarah, Pietka, Terri A, Pino, Maria F, Pirkmajer, Sergej, Plangger, Mario, Porter, Craig, Porter, Richard K, Procaccio, Vincent, Prochownik, Edward V, Prola, Alexandre, Pulinilkunnil, Thomas, Puskarich, Michael A, Puurand, Marju, Radenkovic, Filip, Ramzan, Rabia, Rattan, Suresh IS, Reboredo, Patricia, Renner-Sattler, Kathrin, Rial, Eduardo, Robinson, Matthew M, Roden, Michael, Rodriguez, Enrique, Rodriguez-Enriquez, Sara, Roesland, Gro Vatne, Rohlena, Jakub, Rolo, Anabela Pinto, Ropelle, Eduardo R, Rossignol, Rodrigue, Rossiter, Harry B, Rubelj, Ivica, Rybacka-Mossakowska, Joanna, Saada, Ann, Safaei, Zahra, Sarlak, S, Salin, Karine, Salvadego, Desy, Sandi, Carmen, Saner, Nicholas, Sanz, Alberto, Sazanov, Leonid A, Scatena, Roberto, Schartner, Melanie, Scheibye-Knudsen, Morten, Schilling, Jan M, Schlattner, Uwe, Schoenfeld, Peter, Schots, Pauke C, Schulz, Rainer, Schwarzer, Christoph, Scott, Graham R, Selman, Colin, Shabalina, Irina G, Sharma, Pushpa, Sharma, Vipin, Shevchuk, Igor, Shirazi, Reza, Shiroma, Jonathan G, Siewiera, Karolina, Silber, Ariel M, Silva, Ana Maria, Sims, Carrie A, Singer, Dominique, Singh, Brijesh Kumar, Skolik, Robert A, Smenes, Benedikte Therese, Smith, James, Soares, Félix Alexandre Antunes, Sobotka, Ondrej, Sokolova, Inna, Sonkar, Vijay K, Sowton, Alice P, Sparagna, Genevieve C, Sparks, Lauren M, Spinazzi, Marco, Stankova, Pavla, Starr, Jonathan, Stary, Creed, Stelfa, Gundega, Stepto, Nigel K, Stiban, Johnny, Stier, Antoine, Stocker, Roland, Storder, Julie, Sumbalova, Zuzana, Suomalainen, Wartiovaara Anu, Suravajhala, Prashanth, Svalbe, Baiba, Swerdlow, Russel H, Swiniuch, Daria, Szabo, Ildiko, Szewczyk, Adam, Szibor, Marten, Tanaka, Masashi, Tandler, Bernard, Tarnopolsky, Mark A, Tausan, Daniel, Tavernarakis, Nektarios, Tepp, Kersti, Thakkar, Himani, Thapa, Maheshwo, Thyfault, John P, Tomar, Dhanendra, Ton, Riccardo, Torp, May-Kristin, Towheed, Atif, Tretter, Laszlo, Trewin, Adam J, Trifunovic, Aleksandra, Trivigno, Catherine, Tronstad, Karl Johan, Trougakos, Ioannis P, Truu, Laura, Tuncay, Erkan, Turan, Belma, Tyrrell, Daniel J, Urban, Tomas, Valentine, Joseph Marco, Van Bergen, Nicole J, Van Hove, Johan, Varricchio, Frederick, Vella, Joanna, Vendelin, Marko, Vercesi, Anibal E, Victor, Victor Manuel, Vieira Ligo Teixeira, Camila, Vidimce, Josif, Viel, Christian, Vieyra, Adalberto, Vilks, Karlis, Villena, Joseph A, Vincent, Vinnyfred, Vinogradov, Andrey D, Viscomi, Carlo, Vitorino, Rui Miguel Pinheiro, Vogt, Sebastian, Volani, Chiara, Volska, Kristine, Votion, Dominique-Marie, Vujacic-Mirski, Ksenija, Wagner, Brett A, Ward, Marie Louise, Warnsmann, Verena, Wasserman, David H, Watala, Cezary, Wei, Yau-Huei, Whitfield, Jamie, Wickert, Anika, Wieckowski, Mariusz R, Wiesner, Rudolf J, Williams, Caroline M, Winwood-Smith, Hugh, Wohlgemuth, Stephanie E, Wohlwend, Martin, Wolff, Jonci Nikolai, Wrutniak-Cabello, Chantal, Wuest, Rob C I, Yokota, Takashi, Zablocki, Krzysztof, Zanon, Alessandra, Zanou, Nadege, Zaugg, Kathrin, Zaugg, Michael, Zdrazilova, Lucie, Zhang, Yong, Zhang, Yi Zhu, Zikova, Alena, Zischka, Hans, Zorzano, Antonio, Zvejniece, Liga, Lagarrigue, Sylviane, Munro, Daniel, Pereira, Susana, Laranjinha, Joäo, Almeida, Angeles, Diederich, M, Hecker, M, Jusic, A, Prigione, A, Sommer, N, Weissig, V, Abdel-Rahman, EA, Sova, M, Amorim, R, Beleza, J, Bravo-Sagua, R, Celen, MC, Coxito, P, Crispim, M, Dias, C, Evinova, A, Fuertes Agudo, M, Gao, Y, Garcia, G, Goikoetxea Usandizaga, N, Grilo, L, Minuzzi, LM, Hachmo, Y, Hajrulahovic, A, Hatokova, Z, Henrique, A, Holzner, L, Kimoloi, S, Ledo, AM, Machado, IF, Magalhaes, J, Magri, A, Nunes, S, Oliveira, J, Pinho, SA, Preguica, I, Reano, S, Rodrigues, AS, Santos, D, Sardao, V, Stevanovic, J, Teodoro, J, Van der Ende, M, Zujovic, T, Djafarzadeh, S, Schneider Gasser, EM, Jaspers, RT, Arias-Reyes, C, Bairam, A, Laouafa, S, Marcouiller, F, Soliz, J, Glatz, J, Antunes, D, Bach de Courtade, SM, Bardal, T, Di Paola, FJ, Fulton, M, Grams, B, Joseph, V, Kwon, OS, Liang, L, Mila Guasch, M, Moore, C, Norman, J, O'Brien, K, Olsen, RE, Paez, H, Rees, BB, Roshanravan, B, Scaife, P, Sendon, PM, Vlachaki Walker, J, Crossland, H, Jones, JG, Bento, G, Perales, JC, and Aragones Lopez, J

Subjects
uncoupling, Mitochondrial respiratory control, coupling control, protonmotive force, oxidative phosphorylation, mitochondrial respiratory control, NARILIS, ET [electron transfer], electron transfer, residual oxygen consumption, flux, normalization, efficiency, flow, oxygen, mitochondrial preparations, proton leak
Abstract

As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow guidelines of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of databases of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.

Published
2019
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4. Subclassification of fatty liver by its pathogenesis: cIEFing is believing

Author

Byrne, Frances L and Hoehn, Kyle L

Subjects
Immunoassay, Proteomics, Glycosylation, Age Factors, Proteins, Acetylation, Mice, Transgenic, Article, High-Throughput Screening Assays, Mice, Inbred C57BL, Fatty Liver, Disease Models, Animal, Mice, Phenotype, Liver, Animals, Genetic Predisposition to Disease, Isoelectric Focusing, Phosphorylation, Protein Processing, Post-Translational, Biomarkers
Abstract

Fatty liver, also termed hepatic steatosis or fatty liver disease, is a condition characterized by excess fat accumulation in the liver. Common causes of fatty liver include obesity, ageing, medications, genetic disorders, viral hepatitis, excess alcohol or toxins. This diversity in pathogenesis is matched by an equally diverse spectrum of consequences, whereby some individuals remain asymptomatic yet others progress through a series of inflammatory, fibrotic and metabolic disorders that can lead to liver failure, cancer or diabetes. Current treatment approaches for fatty liver do not differ by disease aetiology and primarily involve weight loss strategies or management of co-morbidities. In a recent paper published in this journal, Urasaki et al used capillary isoelectric focusing (cIEF) to create profiles of protein post-translational modifications that distinguish four different models of fatty liver in mice. Importantly, this new cIEF approach has the potential to provide rapid individualized diagnosis of fatty liver pathogenesis that may enable more accurate and personalized treatment strategies. Further testing and optimization of cIEF as a diagnostic screening tool in humans is warranted.

Published
2016

5. Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance

Author

Fazakerley, Daniel J, Chaudhuri, Rima, Yang, Pengyi, Maghzal, Ghassan J, Thomas, Kristen C, Krycer, James R, Humphrey, Sean J, Parker, Benjamin L, Fisher-Wellman, Kelsey H, Meoli, Christopher C, Hoffman, Nolan J, Diskin, Ciana, Burchfield, James G, Cowley, Mark J, Kaplan, Warren, Modrusan, Zora, Kolumam, Ganesh, Yang, Jean Yh, Chen, Daniel L, Samocha-Bonet, Dorit, Greenfield, Jerry R, Hoehn, Kyle L, Stocker, Roland, and James, David E

Subjects
medicine, Mitochondrial Diseases, Muscle Weakness, Ubiquinone, Muscles, food and beverages, human biology, Coenzyme Q, Insulin resistance, Oxidants, Sensitivity and Specificity, 3. Good health, Mitochondria, Mice, Adipose Tissue, cell biology, Adipocytes, Insulin, Animals, Humans, Ataxia, human, mouse
Abstract

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance.

6. The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes

Author

Rima Chaudhuri, Zdenka Kuncic, Daniel J. Fazakerley, Kyle L. Hoehn, David E. James, James R. Krycer, Fatemeh Vafaee, Kelsey H. Fisher-Wellman, Zhiduan Su, Jean Yee Hwa Yang, Fazakerley, Daniel J [0000-0001-8241-2903], Hoehn, Kyle L [0000-0002-0214-3238], Kuncic, Zdenka [0000-0001-6765-3215], Vafaee, Fatemeh [0000-0002-7521-2417], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Transcription, Genetic, medicine.medical_treatment, lcsh:Medicine, Type 2 diabetes, Deoxyglucose, Biology, Carbohydrate metabolism, medicine.disease_cause, Article, Cell Line, Mice, 03 medical and health sciences, Insulin resistance, 3T3-L1 Cells, Adipocytes, medicine, Animals, Insulin, lcsh:Science, Transcription factor, Multidisciplinary, lcsh:R, medicine.disease, Cell biology, Oxidative Stress, Glucose, 030104 developmental biology, Diabetes Mellitus, Type 2, lcsh:Q, Insulin Resistance, Signal transduction, Thioredoxin, Oxidative stress, Signal Transduction
Abstract

Insulin resistance is a major risk factor for metabolic diseases such as Type 2 diabetes. Although the underlying mechanisms of insulin resistance remain elusive, oxidative stress is a unifying driver by which numerous extrinsic signals and cellular stresses trigger insulin resistance. Consequently, we sought to understand the cellular response to oxidative stress and its role in insulin resistance. Using cultured 3T3-L1 adipocytes, we established a model of physiologically-derived oxidative stress by inhibiting the cycling of glutathione and thioredoxin, which induced insulin resistance as measured by impaired insulin-stimulated 2-deoxyglucose uptake. Using time-resolved transcriptomics, we found > 2000 genes differentially-expressed over 24 hours, with specific metabolic and signalling pathways enriched at different times. We explored this coordination using a knowledge-based hierarchical-clustering approach to generate a temporal transcriptional cascade and identify key transcription factors responding to oxidative stress. This response shared many similarities with changes observed in distinct insulin resistance models. However, an anti-oxidant reversed insulin resistance phenotypically but not transcriptionally, implying that the transcriptional response to oxidative stress is insufficient for insulin resistance. This suggests that the primary site by which oxidative stress impairs insulin action occurs post-transcriptionally, warranting a multi-level ‘trans-omic’ approach when studying time-resolved responses to cellular perturbations.

Published
2018
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