Abstract
Obesity is becoming a global threat, not only reducing female fertility but also affecting the offspring's health. The quality of the oocytes developing under obesity-associated metabolic stress is significantly deteriorated, mainly due to oxidative stress (OS) and mitochondrial (MT) dysfunction. The defective mitochondria are transferred to the embryo, with persistently high OS levels, leading to transcriptomic, epigenetic and phenotypic alterations, and low pregnancy rates, even when clinical assisted reproductive treatments are used. Early embryos lack the machinery to re-establish cellular homeostasis or activate mitophagy and mitogenesis to rejuvenate MT functions and support embryo survival. Current clinical interventions during the preconception period, such as diet caloric normalization or restriction, have been shown to restore systemic metabolic health but fail to rescue oocyte MT functions. Emerging MT-targeted antioxidants and compounds inducing mitophagy have been proven efficient in combating MT dysfunction in several metabolic diseases. These treatments could enhance oocyte quality when supplemented in vitro, however their efficiency to enhance MT functions in metabolically stressed oocytes from obese females in vivo has not been previously investigated, yet very topical and important. In this project we hypothesize that treatments with pharmaceutical compounds can specifically support MT functions in oocytes. A targeted reduction of MT oxidative stress or activation of mitophagy and mitogenesis during the preconception period in obese females can improve oocyte quality and oocyte developmental competence. We believe that this approach will also improve embryo quality and normalize epigenetic programming during subsequent development resulting in better offspring health. Therefore, we firstly aim to enhance oocyte MT functions and quality in vivo in obese females using MitoQ, a MT targeted antioxidant (i.e. for MT TARGETED SUPPORT), or Liraglutide, a potent anti-diabetic medication increasingly used for weight management, known to stimulate mitophagy via SIRT1-PINK1-Parkin dependent ubiquitin pathway (i.e. for REPAIR and REJUVINATION). We will use a validated outbred Swiss mouse model to increase the pathophysiological relevance to the humans. Secondly, we aim to test and compare the efficiency of different MT-targeted therapies when supplemented in vitro during culture of embryos derived from mature oocytes collected from obese mice (EMBRYO RESCUE). We will compare the effects of MitoQ, Liraglutide, as well as Rapamycin to induce mitophagy by inhibiting the mTOR-TORC1 pathways. In addition, we will examine if the MT therapy could alleviate obesity-induced epigenetic alterations in the produced embryos. Lastly and most importantly, we are also planning to follow up the effect of the treatments on offspring health after embryo transfer, an insight which is lacking in the majority of studies in this field. Taken the pandemic burden of obesity and metabolic disorders, this fundamental insight is needed as a basis to develop efficient strategies to improve human fertility at the time of conception by targeting oocyte mitochondria. We furthermore need this evidence-based proof of concept to prioritize the health outcomes in the children born from obese mothers. The project benefits from the combined expertise of the research team at the Gamete Research centre, lead by Prof. Jo Leroy, as well as the expertise in autophagy screening and targeting provided by Prof. Wim Martinet (Laboratory of Physiopharmacology).
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