Coordinated reprogramming of metabolism and cell function in adipocytes from proliferation to differentiation |
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| Institution: | 1. US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA;2. Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA;3. USDA Agricultural Research Service, Wheat Health, Genetics and Quality, Washington State University, Pullman, WA, USA;4. Department of Plant Pathology, Washington State University, Pullman, WA, USA;5. Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA;6. Center for Advanced Bioenergy and Bioproducts Innovation, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA;7. Global Center for Food, Land, and Water Resources, Hokkaido University, Hokkaido, 060-8589, Japan;1. Mathematics and Computer Science Division, Argonne National Laboratory, Argonne, IL, 60439, USA;2. Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, 60637, USA;3. Department of Data Science and Learning, Argonne National Laboratory, Argonne, IL, 60439, USA;4. Department of Carcinogenesis and Oncogerontology, N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg, 197758, Russia;5. Horticultural Sciences Department, University of Florida, Gainesville, FL, 32611, USA;6. Plant and Microbial Biology Department, University of Minnesota, Saint Paul, MN, 55108, USA;7. West Coast Metabolomics Center, University of California, Davis, CA, USA;8. Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, 60208, USA;1. Department of Life Sciences and Chemistry, Jacobs University Bremen gGmbH, Campus Ring 1, 28759, Bremen, Germany;2. Institute of Biochemical Engineering, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany;3. iBB – Institute for Bioengineering and Biosciences/i4HB-Associate Laboratory Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal;4. Chair of Microbiology, TUM School of Life Sciences, Technical University of Munich, Emil-Ramann-Str 4, 85354, Freising-Weihenstephan, Germany;5. NGS Competence Center Tübingen, Universitätsklinikum Tübingen, Calwerstraße 7, 72076, Tübingen, Germany;6. VTT Technical Research Centre of Finland Ltd., P.O. Box 1000, 02044, VTT Espoo, Finland;7. NovelYeast bv, Open Bio-Incubator, Erasmus High School, Laarbeeklaan 121, 1090, Brussels (Jette), Belgium;8. Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal;1. Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China;2. Key Laboratory of Systems Microbial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China |
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| Abstract: | Adipose tissue plays a major role in regulating lipid and energy homeostasis by storing excess nutrients, releasing energetic substrates through lipolysis, and regulating metabolism of other tissues and organs through endocrine and paracrine signaling. Adipocytes within fat tissues store excess nutrients through increased cell number (hyperplasia), increased cell size (hypertrophy), or both. The differentiation of pre-adipocytes into mature lipid-accumulating adipocytes requires a complex interaction of metabolic pathways that is still incompletely understood. Here, we applied parallel labeling experiments and 13C-metabolic flux analysis to quantify precise metabolic fluxes in proliferating and differentiated 3T3-L1 cells, a widely used model to study adipogenesis. We found that morphological and biomass composition changes in adipocytes were accompanied by significant shifts in metabolic fluxes, encompassing all major metabolic pathways. In contrast to proliferating cells, differentiated adipocytes 1) increased glucose uptake and redirected glucose utilization from lactate production to lipogenesis and energy generation; 2) increased pathway fluxes through glycolysis, oxidative pentose phosphate pathway and citric acid cycle; 3) reduced lactate secretion, resulting in increased ATP generation via oxidative phosphorylation; 4) rewired glutamine metabolism, from glutaminolysis to de novo glutamine synthesis; 5) increased cytosolic NADPH production, driven mostly by increased cytosolic malic enzyme flux; 6) increased production of monounsaturated C16:1; and 7) activated a mitochondrial pyruvate cycle through simultaneous activity of pyruvate carboxylase, malate dehydrogenase and malic enzyme. Taken together, these results quantitatively highlight the complex interplay between pathway fluxes and cell function in adipocytes, and suggest a functional role for metabolic reprogramming in adipose differentiation and lipogenesis. |
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| Keywords: | Adipocytes Differentiation Metabolism 3T3-L1 cells Adipogensis |
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