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Overexpression of Des(1–3) Insulin-Like Growth Factor 1 in the Mammary Glands of Transgenic Mice Delays the Loss of Milk Production with Prolonged Lactation¹

USDA/ARS Children's Nutrition Research Center,³ Department of Pediatrics The Breast Center, Department of Medicine,⁴ and Department of Molecular and Cellular Biology,⁵ Baylor College of Medicine, Houston, Texas 77030 National Hormone Peptide Program,⁶ Harbor-UCLA Medical Center, Torrance, California 90509

ABSTRACT

During prolonged lactation, the mammary gland gradually loses the capacity to produce milk. In agricultural species, this decline can be slowed by administration of exogenous growth hormone (GH), which is believed to act through insulin-like growth factor 1 (IGF1). Our previous work demonstrated delayed natural mammary gland involution in des(1–3)IGF1-overexpressing transgenic mice (Tg[Wap-des{1–3}IGF1]8266 Jmr), hereafter referred to as WAP-DES mice. The present study tested the hypothesis that overexpressed des(1–3)IGF1 would delay the loss of milk production during prolonged lactation. Accordingly, we examined lactational performance in WAP-DES mice by artificially prolonging lactation with continual litter cross-fostering. Over time, lactational capacity and mammary development declined in both WAP-DES and control mice. However, the rate of decline was 40% slower in WAP-DES mice. Mammary cell apoptosis increased by 3-fold in both groups during prolonged lactation but was not different between genotypes. Plasma concentrations of murine IGF1 were decreased in WAP-DES mice, while those of the transgenic human IGF1 were elevated during prolonged lactation. Phosphorylation of the mammary IGF1 receptor was increased in the WAP-DES mice, but only during prolonged lactation. Plasma prolactin decreased with prolonged lactation in nontransgenic mice but remained high in WAP-DES mice. The WAP-DES mice maintained a higher body mass and a greater lean body mass during prolonged lactation. These data support the conclusion that overexpressed des(1–3)IGF1 enhanced milk synthesis and mammary development during prolonged lactation through localized and direct activation of the mammary gland IGF1 receptor and through systemic effects on prolactin secretion and possibly nutrient balance.

insulin-like growth factor receptor, kinases, lactation, mechanisms of hormone action, prolactin, persistence, transgenic

¹ Supported by USDA NRI grant 2001–35206–11145 (D.L.H.) and by NIH grant DK52197 (D.L.H.), and NIH grant CA94118 (A.V.L.). This work is a publication of the United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine Texas Children's Hospital, Houston, Texas. The contents of this publication do not necessarily reflect the views or policies of the United States Department of Agriculture, nor does the mention of any trade names, commercial products, or organizations imply endorsement by the United States government.

² Correspondence: Darryl L. Hadsell, USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, 1100 Bates St., Houston, TX 77030. FAX: 713 798 7057; dhadsell{at}bcm.tmc.edu

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				D. L Hadsell, A. F Parlow, D. Torres, J. George, and W. Olea Enhancement of maternal lactation performance during prolonged lactation in the mouse by mouse GH and long-R3-IGF-I is linked to changes in mammary signaling and gene expression J. Endocrinol., July 1, 2008; 198(1): 61 - 70. [Abstract] [Full Text] [PDF]

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