Department of Animal Science, Cornell University, Ithaca, New York 14853, USA.
Endocrinology. 2010 Aug;151(8):3985-95. doi: 10.1210/en.2010-0029. Epub 2010 May 25.
Mice lacking leptin (ob/ob) or its full-length receptor (db/db) are obese and reproductively incompetent. Fertility, pregnancy, and lactation are restored, respectively, in ob/ob mice treated with leptin through mating, d 6.5 post coitum, and pregnancy. Therefore, leptin signaling is needed for lactation, but the timing of its action and the affected mammary process remain unknown. To address this issue, we used s/s mice lacking only leptin-dependent signal transducer and activator of transcription (STAT)3 signaling. These mice share many features with db/db mice, including obesity, but differ by retaining sufficient activity of the hypothalamic-pituitary-ovarian axis to support reproduction. The s/s mammary epithelium was normal at 3 wk of age but failed to expand through the mammary fat pad (MFP) during the subsequent pubertal period. Ductal growth failure was not corrected by estrogen therapy and did not relate to inadequate IGF-I production by the MFP or to the need for epithelial or stromal leptin-STAT3 signaling. Ductal growth failure coincided with adipocyte hypertrophy and increased MFP production of leptin, TNFalpha, and IL6. These cytokines, however, were unable to inhibit the proliferation of a collection of mouse mammary epithelial cell lines. In conclusion, the very first step of postnatal mammary development fails in s/s mice despite sufficient estrogen IGF-I and an hypothalamic-pituitary-ovarian axis capable of supporting reproduction. This failure is not caused by mammary loss of leptin-dependent STAT3 signaling or by the development of inflammation. These data imply the existence of an unknown mechanism whereby leptin-dependent STAT3 signaling and obesity alter mammary ductal development.
瘦素缺乏（ob/ob）或其全长受体（db/db）的小鼠肥胖且生殖无能。通过交配、受精后 6.5 天和妊娠，分别用瘦素治疗 ob/ob 小鼠，可恢复生育力、妊娠和哺乳。因此，瘦素信号传导对于哺乳是必需的，但作用的时间及其影响的乳腺过程仍然未知。为了解决这个问题，我们使用了仅缺乏瘦素依赖性信号转导和转录激活因子（STAT）3 信号传导的 s/s 小鼠。这些小鼠与 db/db 小鼠有许多共同特征，包括肥胖，但通过保留足够的下丘脑-垂体-卵巢轴活性来支持生殖而有所不同。3 周龄时，s/s 乳腺上皮正常，但在随后的青春期期间未能通过乳腺脂肪垫（MFP）扩张。雌激素治疗不能纠正导管生长失败，与 MFP 产生不足的 IGF-I 无关，也与上皮或基质瘦素-STAT3 信号传导无关。导管生长失败与脂肪细胞肥大和 MFP 产生增加的瘦素、TNFalpha 和 IL6 同时发生。然而，这些细胞因子无法抑制一系列小鼠乳腺上皮细胞系的增殖。总之，尽管有足够的雌激素 IGF-I 和能够支持生殖的下丘脑-垂体-卵巢轴，s/s 小鼠的产后乳腺发育的第一步仍然失败。这种失败不是由于乳腺中瘦素依赖性 STAT3 信号传导的丧失或炎症的发展引起的。这些数据表明，存在一种未知的机制，通过该机制，瘦素依赖性 STAT3 信号传导和肥胖改变乳腺导管发育。
