In vitro model of human subcutaneous adipocyte spheroids for studying mitochondrial dysfunction and mitochondria activating compounds - UTU Research Portal

A1 Refereed original research article in a scientific journal

In vitro model of human subcutaneous adipocyte spheroids for studying mitochondrial dysfunction and mitochondria activating compounds

Authors: Wagner, Anita; Lautaoja-Kivipelto, Juulia H.; Pehkonen, Kalle; Hassinen, Antti; Kuusela, Minna; Röttger, Lisa; Herbers, Elena; Ioannidou, Anna; Mädler, Sophia; Rothenaigner, Ina; Srinivasan, Soumya; Laasonen, Sini; Rahman, M. Tanvir; Elomaa, Pinja; Kortetjärvi, Saija; Olsson, Anneli; Ukkola, Olavi; Hadian, Kamyar; Mann, Matthias; Peltoniemi, Hilkka; Pietiläinen, Kirsi H.; Klingenspor, Martin; Virtanen, Kirsi A.; Hagberg, Carolina E.; Pirinen, Eija

Publisher: Elsevier BV

Publication year: 2026

Journal: iScience

Article number: 114480

Volume: 29

Issue: 2

eISSN: 2589-0042

DOI: https://doi.org/10.1016/j.isci.2025.114480

Publication's open availability at the time of reporting: Open Access

Publication channel's open availability : Open Access publication channel

Web address : https://doi.org/10.1016/j.isci.2025.114480

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/515510477

Self-archived copy's licence: CC BY

Self-archived copy's version: Publisher`s PDF

Abstract

Mitochondrial abnormalities drive subcutaneous white adipose tissue dysfunction in obesity, yet in vitro models to study adipocyte mitochondria remain limited. Here, we establish a human subcutaneous adipocyte spheroid model to characterize mitochondrial metabolism under obesity-relevant conditions and drug exposure. Human preadipocyte spheroids were differentiated in ultra-low attachment plates for 3 weeks using thiazolidinedione-free medium. Matrigel embedding was incorporated into the protocol as it promoted mitochondrial network and respiration compared to scaffold-free conditions. Differentiated spheroids showed increased lipid accumulation, adipogenic gene expression, mitochondrial respiration, adiponectin secretion, and hormonal responsiveness. Lipid mixture administration during differentiation induced metabolic disturbances, including mitochondrial respiration failure, alongside increased mitochondrial biogenesis. Post-differentiation treatment with rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, improved mitochondrial bioenergetics and adiponectin secretion in lipid mixture-administered adipocyte spheroids. Our model enables precise measurement of adipocyte mitochondria metabolism, providing a platform for mitochondria-focused research and drug discovery in obesity.

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Funding information in the publication:
This work was supported by the Academy of Finland/Research Council of Finland (335445, 335446, 314455, 314456, 266286, 272376, 314383, and 335443), Finnish Medical Foundation, Finnish Diabetes Research Foundation, Suorsa Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (NNF20OC0060547, NNF17OC0027232, NNF10OC1013354), Paulo Foundation, Sigrid Jusélius Foundation, Government Research Funds, Research Council of Finland Profi6 funding (336449) awarded to the University of Oulu. C.E.H. was supported by Karolinska Institutet (2-1062/2018 and 2-189/2022) and Diabetes Wellness Sweden (DWPG-2022-0032). A.W. was awarded a young investigator start-up project funded by the Deutsche Forschungsgemeinschaft (CRC-TRR333 BATenergy). Open access was funded by Helsinki University Library.