The effects of voluntary exercise on oocyte quality in a diet-induced obese murine model

Abstract

Obesity negatively affects many aspects of the human body, including reproductive function. In females, the root of the decline in fertility is linked to problems in the oocyte. Problems seen in oocytes that positively correlate with increasing BMI include changes to the metabolism, lipid accumulation, meiosis, and metaphase II (MII) spindle structure. Studies in mice indicate dietary interventions fail to reverse these problems [4]. How exercise affects the oocytes has not been addressed. Therefore, we hypothesized an exercise intervention would improve oocyte quality. Here we show in a mouse model of an exercise intervention can improve lipid metabolism in germinal vesicle (GV) stage oocytes. Oocytes significantly increased activity and transcription of the β-oxidation enzyme Hadha (Hydroxyacyl-CoA-dehydrogenase) in response to exercise training only if the mice had been fed a high fat diet (HFD). An exercise intervention also reversed the lipid accumulation seen in GV stage oocytes of HFD females. However, delays in meiosis and disorganized MII spindles remained present. Therefore, exercise is able to improve, but not reverse, damage imparted on oocytes as a result of a high fat diet and obesity. By utilizing an exercise intervention on a HFD, we determined only lipid content and lipid metabolism is changed in GV oocytes. Moving forward, interventions to improve oocyte quality may need to be more targeted to the oocyte specifically. Because of the HFD induced deficiency in β-oxidation, dietary supplementation with substrates to improve lipid utilization may be more beneficial.

Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Generations

“…Four-week-old female C57Bl/6 mice were fed either a high-fat/ high-sugar (HF/HS) (Test Diet 58R3; 59% fat, 26% carbohydrates [17% sucrose] and 15% protein) or standard chow (Con) (PicoLab Rodent diet 20; 13% fat, 62% carbohydrates [3.2% sucrose] and 25% protein for six weeks (Boudoures et al, 2016; Reynolds et al, 2015). Con- and HF/HS-fed F0 mice were mated with chow-fed male mice to produce the first generation.…”

“…Briefly, we demonstrated that female mice with diet-induced metabolic syndrome had abnormal oocyte mitochondrial morphology characterized by fewer, more disarrayed cristae, decreased electron density of the matrix, increased swelling, and more vacuoles (Luzzo et al, 2012). Additionally, oocyte mitochondria from mice fed a high fat-high sugar (HF/HS) were less round and more dumbbell shaped than their chow-fed counterparts, suggesting a defect in mitochondrial dynamics (Boudoures et al, 2016). These defects in mitochondrial morphology were accompanied by impaired beta oxidation (Boudoures et al, 2016), decreased mitochondrial membrane potential (Reynolds et al, 2015), and altered ATP and citrate levels (Boudoures et al, 2016; Luzzo et al, 2012; Reynolds et al, 2015).…”

“…Additionally, oocyte mitochondria from mice fed a high fat-high sugar (HF/HS) were less round and more dumbbell shaped than their chow-fed counterparts, suggesting a defect in mitochondrial dynamics (Boudoures et al, 2016). These defects in mitochondrial morphology were accompanied by impaired beta oxidation (Boudoures et al, 2016), decreased mitochondrial membrane potential (Reynolds et al, 2015), and altered ATP and citrate levels (Boudoures et al, 2016; Luzzo et al, 2012; Reynolds et al, 2015). Adult offspring bore to obese mothers developed characteristics of metabolic syndrome (Jungheim et al, 2010), suggesting that the maternal germline can transmit changes to offspring metabolic function.…”

Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract

“…For example, obese mice experience infertility and one mechanism is that oocyte development is impeded resulting in aberrant spindle formation. Reversal of the obesity by diet alone or by exercise does not eliminate the spindle disorders (Reynolds et al, 2015;Boudoures et al, 2016). The mechanism of obesity-related oocyte damage is not fully elucidated and may involve oxidative damage and abnormal lipid accumulation in the oocyte.…”

Nutritional adversity, sex and reproduction: 30 years of DOHaD and what have we learned?

“…Weight loss, at least in mice, did not show reversal of these negative defects or reverse oocyte lipid accumulation, alterations in TCA cycle metabolite levels and mitochondrial membrane potential, or abnormalities in mitochondrial distribution, despite reversal of the metabolic phenotypes of obesity (Reynolds et al 2015). But effects can be reversed with therapies specifically targeting the mitochondrial respiratory chain (Boots et al 2016) or ER stress, and oocyte competence has been improved with voluntary exercise regimes (Boudoures et al 2016). These impairments in oocytes are associated with poor blastocyst and embryo development, increased ROS production as well as mitochondrial dysfunction in embryos (Igosheva et al 2010, Wu et al 2010, Boudoures et al 2017.…”