Loss ofMfn1but notMfn2enhances adipogenesis

• DOI: 10.1101/2022.11.04.515167
• Publication Date: 2022-11-05T03:00:11Z
• Authors: JP Mann; LC Tabara; A Alvarez-Guaita; L Dong; A Haider; K Lim; P Tandon; JEN Minchin; S O’Rahilly; S Patel; DJ Fazakerley; J Prudent; RK Semple; DB Savage
• Keywords: 0301 basic medicine; 03 medical and health sciences

AbstractObjectiveA 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-/-andMfn2-/-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 includingPpargupregulation.Mfn2-/-MEFs also had a disrupted mitochondrial morphology, but in contrast toMfn1−/-MEFs they showed reduced expression of adipocyte markers and no increase in insulin-stimulated glucose uptake.Mfn1andMfn2siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings.ConclusionsLoss ofMfn1but notMfn2in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.