Role of mitochondria-endoplasmic reticulum interaction on maternal inheritance of metabolic syndromes

Abstract

Growing evidence supports that maternal obesity predisposes 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 involving humans and mice have found that metabolic disease represses mitofusin 2 (MFN2) expression, further impacting mitochondria-ER contact sites (MERCs) in tissues such as the skeletal muscle and liver. MFN2 is the 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 is associated with oocytes with abnormal MERCs as well as mitochondrial and ER dysfunction. Given the importance of these findings, here we propose to investigate the impact of maternal obesity combined with oocyte-specific MFN2 deficiency on offspring glucose metabolism. 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. Females will be mated to wild-type males aiming to assess their fertility and analyze progeny as for body weight, body mass index, food intake, peri-gonadal fat, glucose tolerance, and insulin tolerance. Based on these results, further analyses may be carried out in offspring to explore the molecular mechanism underlying abnormalities. We expect from this work to provide evidence that obesity exacerbates the effects of oocyte-specific deficiency of MFN2, contributing to the maternal transmission of metabolic disease. (AU)