Mammary ductal growth is impaired in mice lacking leptin-dependent signal transducer and activator of transcription 3 signaling.
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.
Thorn
Stephanie R
SR
Department of Animal Science, Cornell University, Ithaca, New York 14853, USA.
Giesy
Sarah L
SL
Myers
Martin G
MG
Boisclair
Yves R
YR
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004958:Estradiol / Q000097:blood / Q000494:pharmacology; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D020738:Leptin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D018836:Inflammation Mediators; D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone