Altered insulin, leptin and ghrelin hormone levels and atypical estrous cycle lengths in two highly fertile mouse lines

Abstract

Mouse models of decreased fertility mainly support scientific knowledge in the field of reproductive biology. In this study, we changed the perspective, using Dummerstorf high‐fertility mouse lines FL1 and FL2 selected for increased reproductive performances that doubled the amount of ovulated oocytes per cycle and the number of offspring per litter compared to an unselected control line (founder population, FZTDU, ctrl). After recent observations, both fertility lines seem to show a lower pregnancy rate compared to ctrl together with an atypical reproductive cycle. We analysed the estrous cycle of those mice, but also plasma levels of insulin, glucagon, leptin and ghrelin that, when irregular, may have an impact on the reproductive cycle length by modifying the GnRH release. We included females of another independent line (DU6P), selected from the same founder population but independently of fertility traits, as an additional model of decreased pregnancy rate. We aim to evaluate if do they use a similar mechanism associated in the regulation of the estrous cycle or implicated in altered pregnancy mechanism compared to control, because they show a similar situation as FL2 line does, even without an increase in fertility parameters. We speculate that FLs’ estrous cycle undergoes changes during the selection period and aim to demonstrate that some hormonal dysfunctions link with altered reproductive cycle, dampened pregnancy rates and reduced first delivery rates mostly in FL2, but also with higher‐fertility phenotype rather than lower in both FLs.

Lower Plasmatic Levels of Saturated Fatty Acids and a Characteristic Fatty Acid Composition in the Ovary Could Contribute to the High-Fertility Phenotype in Dummerstorf Superfertile Mice

“…After more than 50 years of selection, both fertility lines doubled the number of pups per litter from approximately 11.5/litter in the control to approximately 20.6 and 21.4 for FL1 and FL2, respectively, due to an increase in their ovulation rates [ 2 , 3 , 5 , 6 ]. Females of Dummerstorf lines managed to reach this goal of higher ovulation rates, increasing the number of high-quality oocytes per ovary compared to the control [ 15 ], even showing alterations in some metabolic hormones, such as leptin, insulin, and glucagon, connected with their nonconventional reproductive cycle [ 14 ].…”

“…The fatty acid panel in the liver analyzed by heatmap and PCA (provided on request) again shows clusters by line, with FL1 revealing the largest differences, including higher OA and a lower AA, DHA, and AA/EPA ratio. As higher levels of SFAs can cause more severe oxidative stress but higher levels of unsaturated FAs cause serious lipid accumulation [ 38 ], this could play a role in their hepatomegaly together with the higher plasma levels of insulin found earlier [ 14 , 35 , 39 ]. Moreover, the FL1 line is the only one with lower fat content in plasma than the control, which could be one of the reasons why it is a healthy mouse line, even showing an enlarged liver.…”

“…In Cumulus–oocyte complexes, the similarities are switched to control/FL1 and DU6P/FL2 ( Figure 5 ), which could fit with their similarities in estrous cycle length, even if we did not find specific FAs/line connections. Higher plasma levels of leptin have been described in FL2 mice in comparison to the other lines [ 14 ]. Leptin is linked with increased fat intake, but it is also a modulator of oocyte maturation, as higher leptin levels lead to increased rates of GVBD (germinal vesicle breakdown) and decreased rates of atresia [ 42 ].…”

“…Previous studies have shown a coevolution of high protein and glycogen contents during selection experiments and have identified PTEN as a gatekeeper for muscle mass in middle-aged female DU6P mice [ 47 ]. We included the DU6P line in our study, as those females show a similar and irregular reproductive cycle, together with altered plasma levels of some metabolic hormones, such as insulin and ghrelin, connected with GnRH (gonadotropin-releasing hormone) secretion, as FL mice do [ 14 ]. Those mice interestingly show a higher quantity of follicles per ovary compared with the control and both fertility lines [ 15 ].…”

“…However, our recent study showed how FLs manage to reach the goal of increased offspring and ovulation rates even with hormonal misbalances, disruption of the reproductive cycle, and, sometimes, lower pregnancy rates. Indeed, our experiments demonstrated a correlation between the elongation of some stages of the estrous cycle with higher levels of insulin, leptin, or glucagon (depending on the line) or with an increased time to delivery or lower pregnancy rates [ 14 ]. Furthermore, we demonstrated that the ovaries of these superfertile mouse lines contain an elevated number of high-quality oocytes rather than an increased pool of oocytes.…”