The impact of a maternal and offspring obesogenic diet on daughter’s oocyte mitochondrial ultrastructure and bioenergetic responses. Insights from an outbred mouse model

Abstract

Obesity affects oocyte mitochondrial functions and reduces oocyte quality and fertility. Obesity may also increase the risk of metabolic disorders in the offspring. Children are likely to follow their parents lifestyle and diet, which also contributes to the increased prevelance of obesity across generations. We hypothesise that the impact of obesogenic (OB) diet and obesity on oocyte mitochondrial functions is different in offspring born to obese mothers compared to those born to healthy mothers. To test this hypothesis, we fed a control (C, 10% fat, 7% sugar) or an OB diet (60% fat, 20% sugar) to female mice (for 7 weeks (w)) and then to their female offspring (for 7w after weaning) in a 2 × 2 factorial design (C » C, n = 35, C » OB, n = 35, OB » C n = 49 and OB » OB, n = 50). Unlike many other studies, we used an outbred Swiss mouse model to increase the human pathophysiological relevance. Offspring were sacrificed at 10w and their oocytes were collected. Offspring OB diet increased oocyte lipid droplet content, mitochondrial activity and reactive oxygen species (ROS) levels, altered mitochondrial ultrastructure and reduced oocyte pyruvate consumption. Mitochondrial DNA copy numbers and lactate production remained unaffected. Mitochondrial ultrastructure was the only factor where a significant interaction between maternal and offspring diet effect was detected. The maternal OB background resulted in a small but significant increase in offspring’s oocyte mitochondrial ultrastructural abnormalities without altering mitochondrial inner membrane potential, active mitochondrial distribution, mitochondrial DNA copy numbers, or ROS production. This was associated with reduced mitochondrial complex III and V expression and reduced pyruvate consumption which may be compensatory mechanisms to control mitochondrial inner membrane potential and ROS levels. Therefore, in this Swiss outbred model, while offspring OB diet had the largest functional impact on oocyte mitochondrial features, the mitochondrial changes due to the maternal background appear to be adaptive and compensatory rather than dysfunctional.

Preconception Diet Interventions in Obese Outbred Mice and the Impact on Female Offspring Metabolic Health and Oocyte Quality

“…Previous research has established that a maternal high-fat diet in outbred mice results in increased F1 oocyte MT ultrastructural abnormalities compared to control [38]. In our results, we showed that the percentage of abnormal mitochondria was slightly increased in HF/HS oocytes compared to CONT.…”

“…In the F0 mice, the increase in MT ultrastructural abnormalities in HF/HS compared to CONT was 9%, and this was associated with decreased developmental competence of these oocytes after in vitro fertilization (IVF) [31]. Also, in another study, increased oocyte MT ultrastructural abnormalities were associated with alterations in MT membrane potential (MMP) and reactive oxygen species (ROS) accumulation in oocytes, as well as abnormal lipid droplet accumulation [38]. In contrast, here, in the offspring, the increase in MT ultrastructural abnormalities in HF/HS compared to CONT was only 3.2%.…”

The impact of offspring and maternal obesogenic diets on adult offspring oocyte mitochondrial morphology in primordial and preantral follicles

“…All primordial, primary, and secondary follicles in each section were examined. To compare the oocyte mitochondrial morphology in preantral follicles with the already well described mitochondrial morphology of mature (ovulated) oocytes, few ovulated oocytes were collected of adult C»C offspring, according to the protocol described by Xhonneux [ 25 ].…”

“…In addition, other specific ultrastructural features which clearly illustrate an abnormality or defect in the oocyte mitochondrial were classified separately, such as mitochondria showing loose inner membranes, broken or protruded outer membranes, rose-petal shaped mitochondria, enlarged mitochondria (>1μm), and mitochondria having electron dense foci. These forms were collectively classified here as abnormal mitochondria, as described in mature oocytes by Marei [ 20 ] and Xhonneux [ 25 ].…”

“…Consumption of OB diets was shown to alter the oocyte mitochondrial ultrastructural morphology, for example by increasing mitochondrial vacuolization and altering inner membrane organization, or by inducing mitochondrial elongation [ 20 – 22 ]. This was associated with concurrent alterations in mitochondrial inner membrane potential, reduced ATP production and increased mitochondrial reactive oxygen species (ROS) production [ 23 – 25 ]. Importantly, most of these studies examined the effect of obesity on oocyte quality in fully grown oocytes either in the preovulatory follicles or after ovulation [ 26 ].…”