Declining fertility in the lethal yellow mouse is related to progressive hyperleptinemia and leptin resistance

Abstract

-Mice possessing the lethal yellow mutation (C57BL/6J A y /a) become obese and develop hyperleptinemia and leptin resistance as they age. To determine the relationship between altered leptin physiology and reproductive function in these mice, we compared body weight (BW), serum leptin concentration, ovulation rate, and in vitro blastocyst development among 120-and 180-d-old lethal yellow and black non-mutant (a/a) mice. Estrous female yellow and black mice were mated with fertile black males. Oviducts were flushed ~ 36 h after mating and the recovered embryos were cultured for 96 h. BW, serum leptin levels, and the leptin:BW ratio differed among groups as follows: 180-d yellow > 120-d yellow > 180-d black = 120-d black. Ovulation rate was similar among 120-d yellow and black, and 180-d black mice. Among 180-d yellow mice, five of twelve mice failed to ovulate, but the other seven mice ovulated a similar number of oocytes as their black counterparts (8.4 ± 0.9 versus 8.0 ± 1.3). Non-ovulators had higher (P < 0.05) leptin levels (56.6 ± 1.8 ng·mL -1 ) than ovulators (46.2 ± 3.5), but BW did not differ significantly. Fewer embryos from 180-d yellow mice reached the blastocyst stage in culture than did the embryos from black mice (55% versus 83%, P < 0.05). Moreover, blastocyst development in 180-d old yellow mice negatively correlated with leptin levels (r = -0.797, P = 0.032) and leptin:BW ratio (r = -0.847, P = 0.016), but not with BW. Declining reproductive function in lethal yellow mice appears to be related to increasing levels of leptin and progression of leptin resistance. obesity / leptin / agouti / reproduction

The effect of maternal body condition on in vivo production of zygotes and behavior of delivered offspring in mice

“…Conversely, our results indicate no effect or a positive effect of overnutrition (obesity) on the ovulation and fertilization rates. In accordance with our outcomes, several studies have reported that there are no differences in the number of collected and IVF produced oocytes or the number of isolated zygotes between obese and nonobese donors in both women and experimental animals [3,7,23,24]. There was no effect of overnutrition found on ovulation activity and fertilization rate in vivo and in vitro either in cows or ewes [25][26][27].…”

Diet-Induced Obesity in Male Mice Is Associated with Reduced Fertility and Potentiation of Acrylamide-Induced Reproductive Toxicity1

“…Subsequent studies then demonstrated that leptin replacement therapy rescued the sterility of genetically obese ob/ob male mice [17]. Experiments in obese mice possessing lethal yellow mutations (C57BL/6J-A y /a) demonstrated an association between reduced fertility, leptin resistance, and hyperleptinemia [18]. In contrast, high-fat diet consumption caused obesity in DBA/2J male mice; however, these mice exhibited no impairment in fertility despite enduring insulin resistance and hyperleptinemia [19].…”

Gene Expression Profiling in the Aging Ovary

“…Mice heterozygous for the Lethal Yellow (LY) mutation at the agouti gene locus exhibit distinct characteristics including yellow coat color, adult-onset obesity, insulin resistance (2), hyperleptinemia (3), and accelerated reproductive senescence (3,4). Declining ovarian function in aging LY mice is directly related to progressive obesity and hyperleptinemia (3).…”

“…Declining ovarian function in aging LY mice is directly related to progressive obesity and hyperleptinemia (3). Because of the adult-onset, progressive obesity characteristic of LY mice, these mice more closely mimic typical human obesity than many other mouse models of obesity, e.g.…”

“…ob/ob or db/db mice. Therefore, we have used the obese LY mouse and their lean black littermates to study the effects of aging and progressive obesity on gene expression in the ovary (3,5). …”