Impact of MFN2 deficiency and maternal obesity on the oocyte and the transmission of metabolic syndromes

Abstract

Growing evidence supports that maternal obesity predispose the offspring to metabolic syndromes. In this respect, previous reports have indicated a possible role for mitochondrial and endoplasmic reticulum (ER) dysfunction in oocytes. In parallel, studies in humans and mice have found that metabolic diseases repress mitofusin 2 (MFN2) expression, further impacting mitochondria-ER contact sites (MERCs) in tissues such as the skeletal muscle and liver. MFN2 is a main regulator of mitochondrial metabolism and insulin signaling, playing a key role in the control of MERCs and mitochondrial dynamics. In our recent work, we have shown that oocyte-specific MFN2 knockout (MFN2 KO) results in offspring with glucose intolerance, which was linked to lower insulinemia and impaired insulin signaling in the liver and skeletal muscle. Furthermore, this offspring phenotype associated to oocytes with abnormal MERCs as well as mitochondrial and ER dysfunction. Given the importance of these findings, here we propose to investigate how the interaction between MFN2 deficiency and maternal obesity affect mitochondria, MERCs, methylome and transcriptome in oocytes. Transmission of oocyte abnormalities present in generation F0 will be investigated by analysis of offspring from F1, F2 and F3 generations. Towards this, obesity will be induced in wild-type (WT) and MFN2 KO female mice by use of a high fat diet (HFD). As controls, WT and MFN2 KO females will be fed a normal fat diet (NFD), making up four experimental groups: WT-NFD, WT-HFD, MFN2 KO-NFD e MFN2 KO-HFD. Oocytes from F0 progenitors will be compared as for methylome (whole genome bisulfite sequencing), transcriptome (RNA-Seq) and confocal/transmission electron microscopy of mitochondria (morphology, number, and function) and MERCs (architecture). In addition, F0 females will be mated to wild-type males aiming to verify whether oocytes abnormalities are transmitted to somatic and germ-line tissues of F1, F2 and F3 progeny. We expect from this work to provide evidence that the interaction between MFN2 deficiency and maternal obesity results in oocyte alterations that are inherited by offspring, potentially underpinning the onset of metabolic diseases.