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

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 similar to 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 center dot 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.