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Loss of Mfn1 but not Mfn2 enhances adipogenesis.

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Peer-reviewed

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Abstract

OBJECTIVE: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells. METHODS: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA. RESULTS: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings. CONCLUSIONS: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.

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Acknowledgements: We are grateful for the support of the Cambridge Advanced Imaging Centre (University of Cambridge, UK) for performing, processing, and imaging of transmission electron microscope studies. We also acknowledge the light microscopy of the Mitochondrial Biology Unit. We thank M. Mimmack for his technical assistance with cell culture and assays.

Journal Title

PLoS One

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Journal ISSN

1932-6203
1932-6203

Volume Title

19

Publisher

Public Library of Science (PLoS)

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Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
Sponsorship
Medical Research Council (MC_UU_00015/7)
Wellcome Trust (208363/Z/17/Z)
Medical Research Council (MR/S007091/1)
Wellcome Trust (214274/Z/18/Z)
Wellcome Trust (219417/Z/19/Z)
MRC (MC_UU_00014/5)
BBSRC (BB/W008467/1)
MRC (MC_UU_00028/5)