Loss of Mfn1 but not Mfn2 enhances adipogenesis

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 and no increase in insulin-stimulated glucose uptake. 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.