Loss of Mfn1 but not Mfn2 enhances adipogenesis

Jake P. Mann; Luis Carlos Tábara; Satish Patel; Pushpa Pushpa; Anna Alvarez-Guaita; Liang Dong; Afreen Haider; Koini Lim; Panna Tandon; Fabio Scurria; James E. N. Minchin; Stephen O’Rahilly S.; Daniel J. Fazakerley; Julien Prudent; Robert K. Semple; David B. Savage; Benedetta Ruzzenente

doi:10.1371/journal.pone.0306243

Loss of Mfn1 but not Mfn2 enhances adipogenesis

Jake P. Mann, Luis Carlos Tábara, Satish Patel, Pushpa Pushpa, Anna Alvarez-Guaita, Liang Dong, Afreen Haider, Koini Lim, Panna Tandon, Fabio Scurria, James E. N. Minchin, Stephen O’Rahilly S., Daniel J. Fazakerley, Julien Prudent, Robert K. Semple, David B. Savage, Benedetta Ruzzenente (Editor)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e0306243
Journal	PLOS ONE
Volume	19
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0306243
Publication status	Published - 31 Dec 2024

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Mann, J. P., Tábara, L. C., Patel, S., Pushpa, P., Alvarez-Guaita, A., Dong, L., Haider, A., Lim, K., Tandon, P., Scurria, F., Minchin, J. E. N., O’Rahilly S., S., Fazakerley, D. J., Prudent, J., Semple, R. K., Savage, D. B., & Ruzzenente, B. (Ed.) (2024). Loss of Mfn1 but not Mfn2 enhances adipogenesis. PLOS ONE, 19(12), Article e0306243. https://doi.org/10.1371/journal.pone.0306243

@article{e5d3df57558b4097902082e1bc96c5a0,

title = "Loss of Mfn1 but not Mfn2 enhances adipogenesis",

abstract = "ObjectiveA 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.MethodsWe 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.ResultsMfn1-/- 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.ConclusionsLoss 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.",

author = "Mann, {Jake P.} and T{\'a}bara, {Luis Carlos} and Satish Patel and Pushpa Pushpa and Anna Alvarez-Guaita and Liang Dong and Afreen Haider and Koini Lim and Panna Tandon and Fabio Scurria and Minchin, {James E. N.} and {O{\textquoteright}Rahilly S.}, Stephen and Fazakerley, {Daniel J.} and Julien Prudent and Semple, {Robert K.} and Savage, {David B.} and Benedetta Ruzzenente",

year = "2024",

month = dec,

day = "31",

doi = "10.1371/journal.pone.0306243",

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T1 - Loss of Mfn1 but not Mfn2 enhances adipogenesis

AU - Mann, Jake P.

AU - Tábara, Luis Carlos

AU - Patel, Satish

AU - Pushpa, Pushpa

AU - Alvarez-Guaita, Anna

AU - Dong, Liang

AU - Haider, Afreen

AU - Lim, Koini

AU - Tandon, Panna

AU - Scurria, Fabio

AU - Minchin, James E. N.

AU - O’Rahilly S., Stephen

AU - Fazakerley, Daniel J.

AU - Prudent, Julien

AU - Semple, Robert K.

AU - Savage, David B.

A2 - Ruzzenente, Benedetta

PY - 2024/12/31

Y1 - 2024/12/31

N2 - ObjectiveA 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.MethodsWe 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.ResultsMfn1-/- 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.ConclusionsLoss 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.

AB - ObjectiveA 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.MethodsWe 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.ResultsMfn1-/- 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.ConclusionsLoss 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.

U2 - 10.1371/journal.pone.0306243

DO - 10.1371/journal.pone.0306243

M3 - Article

SN - 1932-6203

VL - 19

JO - PLOS ONE

JF - PLOS ONE

IS - 12

M1 - e0306243

ER -

Loss of Mfn1 but not Mfn2 enhances adipogenesis

Abstract

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