The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
BACKGROUND & AIMS - Lactation lowers blood glucose and triglycerides, and increases insulin sensitivity. We hypothesized that a longer duration of lactation would be associated with lower prevalence of non-alcoholic fatty liver disease (NAFLD), which is the leading cause of chronic liver disease in the United States.
METHODS - Participants from the Coronary Artery Risk Development in Young Adults cohort study who delivered ≥ 1 child post-baseline (Y0: 1985-1986), and underwent CT quantification of hepatic steatosis 25 years following cohort entry (Y25: 2010-2011) were included (n = 844). The duration of lactation was summed for all post-baseline births, and NAFLD at Y25 was assessed by central review of CT images and defined by liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of hepatic steatosis. Unadjusted and multivariable logistic regression analyses were performed using an a priori set of confounding variables; age, race, education, and baseline body mass index.
RESULTS - Of 844 women who delivered after baseline (48% black, 52% white, mean age 49 years at Y25 exam), 32% reported lactation duration of 0 to 1 month, 25% reported >1 to 6 months, 43% reported more than 6 months, while 54 (6%) had NAFLD. Longer lactation duration was inversely associated with NAFLD in unadjusted logistic regression. For women who reported >6 months lactation compared to those reporting 0-1 month, the odds ratio for NAFLD was 0.48 (95% CI 0.25-0.94; p = 0.03) and the association remained after adjustment for confounders (adjusted odds ratio 0.46; 95% CI 0.22-0.97; p = 0.04).
CONCLUSIONS - A longer duration of lactation, particularly greater than 6 months, is associated with lower odds of NAFLD in mid-life and may represent a modifiable risk factor for NAFLD.
LAY SUMMARY - A longer duration of breastfeeding has been associated with multiple potential health benefits for the mother including reduction in heart disease, diabetes and certain cancers. In this study we found that breastfeeding for longer than 6 months was associated with a lower risk of non-alcoholic fatty liver disease in mid-life.
Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Many developmental functions in marsupials and eutherian mammals are accomplished by different tissues, but similar genes.
BACKGROUND - During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland.
METHODS - We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs).
RESULTS - Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3 dams weighed significantly less when compared to litters nursed by ErbB3 dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3 samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3 aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3 MECs progressively improved between late pregnancy and lactation day 5. We found a compensatory upregulation of ErbB4 activity in ErbB3 mammary glands. Enforced ErbB4 expression alleviated the consequences of ErbB3 ablation in aMECs, while combined ablation of both ErbB3 and ErbB4 exaggerated the phenotype.
CONCLUSIONS - These studies demonstrate that ErbB3, like ErbB4, enhances lactogenic expansion and differentiation of the mammary gland during pregnancy, through activation of Akt and STAT5A, two targets crucial for lactation.
BACKGROUND - Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis.
RESULTS - ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium.
CONCLUSION - Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.
Industrially produced trans-fatty acids (TFAs) consumed in Western diets are incorporated into maternal and fetal tissues and are passed linearly to offspring via breast milk. We hypothesized that TFA exposure in utero and during lactation in infants would promote obesity and poor glycemic control as compared with unmodified fatty acids. We further hypothesized that in utero exposure alone may program for these outcomes in adulthood. To test this hypothesis, we fed female C57/BL6 mice identical Western diets that differed only in cis- or trans-isomers of C18:1 and then aimed to determine whether maternal transfer of TFAs through pregnancy and lactation alters growth, body composition, and glucose metabolism. Mice were unexposed, exposed during pregnancy, during lactation, or throughout pregnancy and lactation to TFA. Body weight and composition (by computed tomography) and glucose metabolism were assessed at weaning and adulthood. Trans-fatty acid exposure through breast milk caused significant early growth retardation (P < .001) and higher fasting glucose (P = .01), but insulin sensitivity was not different. Elevated plasma insulin-like growth factor-1 in mice consuming TFA-enriched milk (P = .02) may contribute to later catch-up growth and leanness and preserved peripheral insulin sensitivity observed in these mice. Mice exposed to TFA in utero underwent rapid early neonatal growth with TFA-free breast milk and had significantly impaired insulin sensitivity (P < .05) and greater abdominal fat (P = .01). We conclude that very early catch-up growth resulted in impaired peripheral insulin sensitivity in this model of diet-related fetal and neonatal programming. Trans-fatty acid surprisingly retarded growth and adiposity while still adversely affecting glucose metabolism.
Copyright 2010 Elsevier Inc. All rights reserved.
We investigated whether nuclear factor kappa B (NF-kappaB), which exhibits a regulated pattern of activity during murine mammary gland development, plays an important role during lactation and involution, when milk production ceases and the gland undergoes apoptosis and re-modeling. We generated a doxycycline inducible transgenic mouse model to activate NF-kappaB specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-kappaB signaling cascade. We found that activation of NF-kappaB during involution resulted in a more rapid reduction in milk levels and increased cleavage of caspase-3, an indicator of apoptosis. We also found that activation of NF-kappaB during lactation with no additional involution signals had a similar effect. The observation that NF-kappaB is a key regulator of milk production led us to investigate the role of NF-kappaB during mastitis, an infection of the mammary gland in which milk loss is observed. Mammary gland injection of E. coli LPS resulted in activation of NF-kappaB and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-kappaB in mammary epithelium. Together, our data reveal that activation of NF-kappaB leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-kappaB signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact.
Transforming growth factor beta (TGF-beta) ligands are known to regulate virgin mammary development and contribute to initiation of post-lactation involution. However, the role for TGF-beta during the second phase of mammary involution has not been addressed. Previously, we have used an MMTV-Cre transgene to delete exon 2 from the Tgfbr2 gene in mammary epithelium, however we observed a gradual loss of T beta RII deficient epithelial cells that precluded an accurate study of the role for TGF-beta signaling during involution timepoints. Therefore, in order to determine the role for TGF-beta during the second phase of mammary involution we have now targeted T beta RII ablation within mammary epithelium using the WAP-Cre transgene [T beta RII(WKO)Rosa26R]. Our results demonstrated that TGF-beta regulates commitment to cell death during the second phase of mammary involution. Importantly, at day 3 of mammary involution the Na-Pi type IIb co-transporter (Npt2b), a selective marker for active lactation in luminal lobular alveolar epithelium, was completely silenced in the WAP-Cre control and T beta RII(WKO)Rosa26R tissues. However, by day 7 of involution the T beta RII(WKO)Rosa26R tissues had distended lobular alveoli and regained a robust Npt2b signal that was detected at the apical luminal surface. The Npt2b abundance and localization positively correlated with elevated WAP mRNA expression, suggesting that the distended alveoli were the result of an active lactation program rather than residual milk protein and lipid accumulation. In summary, the results suggest that an epithelial cell response to TGF-beta signaling regulates commitment to cell death and suppression of lactation during the second phase of mammary involution.
(c) 2008 Wiley-Liss, Inc.
UNLABELLED - EtOH consumption significantly impaired anabolic rebuilding of bone after lactation. Lower BMD and BMC in EtOH-fed rats were associated with decreased bone formation in the proximal tibia, increased proportion of adipocytes, and increased expression of TNF-alpha. EtOH-induced skeletal deficits were prevented by treatment with either NAC or sTNFR1. These data suggest that postlactational anabolic rebuilding is influenced by EtOH consumption and may affect the long-term risk of osteopenia.
INTRODUCTION - Despite significant loss of bone during lactation, BMD is restored by a powerful anabolic rebuilding process after weaning. A significant number of women resume alcohol consumption after weaning their offspring from breast feeding. The objectives of this study were to examine the consequences of chronic ethanol (EtOH) consumption on the postlactational rebuilding process and to investigate the underlying mechanisms by which EtOH mediates its detrimental effects.
MATERIALS AND METHODS - Female Sprague-Dawley rats (n = 7-9 per group) were fed EtOH-containing diets (13 g/kg/d) for 1, 2, or 4 wk after weaning of their offspring. Skeletal parameters in the proximal tibia were examined using pQCT, microCT, and histomorphometric techniques, and interventional studies were performed on the mechanistic roles of EtOH-induced oxidative stress and TNF-alpha.
RESULTS AND CONCLUSIONS - EtOH consumption completely abolished the anabolic bone rebuilding that occurred after lactation. Decreased BMD and BMC were associated with decreased bone formation and not with increased osteoclast activity. Furthermore, EtOH-fed rats showed greater proportion of fat volume/bone volume and expression of adipocyte-specific genes. EtOH-induced skeletal effects were mitigated by the dietary antioxidant, N-acetyl cysteine or by blocking TNF-alpha signaling. These data suggest EtOH consumption in the period immediately postweaning may significantly impair the mother's skeletal health and lead to long-term osteopenia.
Autosomal dominant polycystic kidney disease, caused by mutations in the PKD1 gene, is characterized by progressive deterioration of kidney function due to the formation of thousands of cysts leading to kidney failure in mid-life or later. How cysts develop and grow is currently unknown, although extensive research revealed a plethora of cellular changes in cyst lining cells. We have constructed a tamoxifen-inducible, kidney epithelium-specific Pkd1-deletion mouse model. Upon administration of tamoxifen to these mice, a genomic fragment containing exons 2-11 of the Pkd1-gene is specifically deleted in the kidneys and cysts are formed. Interestingly, the timing of Pkd1-deletion has strong effects on the phenotype. At 1 month upon gene disruption, adult mice develop only a very mild cystic phenotype showing some small cysts and dilated tubules. Young mice, however, show massive cyst formation. In these mice, at the moment of gene disruption, cell proliferation takes place to elongate the nephron. Our data indicate that Pkd1 gene deficiency does not initiate sufficient autonomous cell proliferation leading to cyst formation and that additional stimuli are required. Furthermore, we show that one germ-line mutation of Pkd1 is already associated with increased proliferation.
Hormonally-linked adult reproductive and anthropometric risk factors have been well established in the etiology of postmenopausal breast cancer, though early life exposures have been evaluated only more recently. Here, we examine the evidence for associations between lifetime reproductive and anthropometric risk factors for postmenopausal breast cancer. The review finds some evidence for the hypothesis that breast cancer risk is determined by the number of susceptible stem cells, modified by the hormonal environment. The in utero experience of an infant may be associated with postmenopausal breast cancer; preeclampsia may decrease and greater birthweight increase risk, but more evidence is needed. Earlier and more rapid childhood growth appears to increase postmenopausal breast cancer risk and childhood obesity to decrease risk, but very few studies have yet examined these associations. Increased final height and earlier age at menarche are consistently associated with increased risk for postmenopausal breast cancer. Later age at first birth, decreased parity, later menopausal age, use of hormone replacement therapy (especially progestin containing), and increased postmenopausal adiposity are well-established risk factors for postmenopausal breast cancer. The effect of a woman's own pregnancy conditions and lactation are not established. Further investigation is needed to identify whether events occurring early in life modify later events or accumulate over the life course. Many aspects of this research can be conducted by examining the influence of early life events on intermediary events without the need for longitudinal data.