Abstract
Background:
Despite successful preclinical testing, 85% of early clinical trials for novel drugs fail. Most futilities originate from molecular mechanisms of the drug(s) tested. It is critically important to develop validated human cell-based model systems in which animal-based research can be translated in order to complement the preclinical in vivo findings prior to implementation of a clinical trial. Obesity is associated with reduced circulating levels of Orexin-A (OX-A) in humans. OX-A increases thermogenesis in rodent brown adipose tissue (AT), yet this phenomenon has not been explored in humans.
Methods:
We established a cell-based model system of human brown and white adipocytes and tested the effects of OX-A on thermogenesis.
Results:
Contrary to published in vivo and in vitro reports in rodents, OX-A treatment alone or in combination with an adrenergic stimulus did neither enhance thermogenesis nor its related transcriptional program in a human in vitro model of brown adipocytes or AT explants.
Conclusions:
Translating preclinical findings in human model systems poses a challenge that must be overcome for the development of effective therapeutic compounds and targets.
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Acknowledgements
We thank the study volunteers and patients for their participation. This study was funded by an internal Strategic Protocol from the Translational Research Institute for Metabolism and Diabetes (no. TRI-SP-14-01) (to LMS).
Author contributions
Conceptualization, LMS and SRS; methodology, MFP, AD, AVS and LMS; investigation, MFP, AD, AVS and LMS; writing—original draft, LMS and MFP; writing—review and editing, MFP, AD, AVS, SRS and LMS; funding acquisition, LMS; resources, AVS, SRS and LMS; supervision, LMS.
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Pino, M., Divoux, A., Simmonds, A. et al. Investigating the effects of Orexin-A on thermogenesis in human deep neck brown adipose tissue. Int J Obes 41, 1646–1653 (2017). https://doi.org/10.1038/ijo.2017.155
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DOI: https://doi.org/10.1038/ijo.2017.155
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