title: Obesity impairs lactation performance in mice by inducing prolactin resistance.
abstract: Obesity reduces breastfeeding success and lactation performance in women. However, the mechanisms involved are not entirely understood. In the present study, female C57BL/6 mice were chronically exposed to a high-fat diet to induce obesity and subsequently exhibited impaired offspring viability (only 15% survival rate), milk production (33% reduction), mammopoiesis (one-third of the glandular area compared to control animals) and postpartum maternal behaviors (higher latency to retrieving and grouping the pups). Reproductive experience attenuated these defects. Diet-induced obese mice exhibited high basal pSTAT5 levels in the mammary tissue and hypothalamus, and an acute prolactin stimulus was unable to further increase pSTAT5 levels above basal levels. In contrast, genetically obese leptin-deficient females showed normal prolactin responsiveness. Additionally, we identified the expression of leptin receptors specifically in basal/myoepithelial cells of the mouse mammary gland. Finally, high-fat diet females exhibited altered mRNA levels of ERBB4 and NRG1, suggesting that obesity may involve disturbances to mammary gland paracrine circuits that are critical in the control of luminal progenitor function and lactation. In summary, our findings indicate that high leptin levels are a possible cause of the peripheral and central prolactin resistance observed in obese mice which leads to impaired lactation performance.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
authors.forename: Daniella C
authors.initials: DC
authors.lastname: Buonfiglio
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Ramos-Lobo
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000, Brazil.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Freitas
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
authors.forename: Thais T
authors.initials: TT
authors.lastname: Zampieri
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Nagaishi
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000, Brazil.
authors.forename: Magna
authors.initials: M
authors.lastname: Magalhães
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
authors.forename: Jose
authors.initials: J
authors.lastname: Cipolla-Neto
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-000, Brazil.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cella
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
authors.forename: Jose
authors.initials: J
authors.lastname: Donato
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D007774:Lactation / Q000502:physiology*; D020738:Leptin / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D020890:Neuregulin-1 / Q000235:genetics; D009765:Obesity / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D066247:Receptor, ErbB-4 / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D020738:Leptin; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D011388:Prolactin; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4