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Systems biology reveals uncoupling beyond UCP1 in human white fat-derived beige adipocytes
Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Cardiovascular and Metabolic Diseases IMED Biotech Unit, AstraZeneca RandD, Gothenburg, Sweden.
Cardiovascular and Metabolic Diseases IMED Biotech Unit, AstraZeneca RandD, Gothenburg, Sweden.
Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
Cardiovascular and Metabolic Diseases IMED Biotech Unit, AstraZeneca RandD, 431 83 Gothenburg, Sweden.
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2017 (English)In: NPJ systems biology and applications, ISSN 2056-7189, Vol. 3, article id 29Article in journal (Refereed) Published
Abstract [en]

Pharmaceutical induction of metabolically active beige adipocytes in the normally energy storing white adipose tissue has potential to reduce obesity. Mitochondrial uncoupling in beige adipocytes, as in brown adipocytes, has been reported to occur via the uncoupling protein 1 (UCP1). However, several previous in vitro characterizations of human beige adipocytes have only measured UCP1 mRNA fold increase, and assumed a direct correlation with metabolic activity. Here, we provide an example of pharmaceutical induction of beige adipocytes, where increased mRNA levels of UCP1 are not translated into increased protein levels, and perform a thorough analysis of this example. We incorporate mRNA and protein levels of UCP1, time-resolved mitochondrial characterizations, and numerous perturbations, and analyze all data with a new fit-for-purpose mathematical model. The systematic analysis challenges the seemingly obvious experimental conclusion, i.e., that UCP1 is not active in the induced cells, and shows that hypothesis testing with iterative modeling and experimental work is needed to sort out the role of UCP1. The analyses demonstrate, for the first time, that the uncoupling capability of human beige adipocytes can be obtained without UCP1 activity. This finding thus opens the door to a new direction in drug discovery that targets obesity and its associated comorbidities. Furthermore, the analysis advances our understanding of how to evaluate UCP1-independent thermogenesis in human beige adipocytes.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017. Vol. 3, article id 29
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:liu:diva-145036DOI: 10.1038/s41540-017-0027-yPubMedID: 28983409OAI: oai:DiVA.org:liu-145036DiVA, id: diva2:1181521
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-03-10

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Nyman, ElinMelin Rydfalk, RebeckaCedersund, Gunnar
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