Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 3/1/2006
Publication Date: 5/1/2006
Citation: Hadsell, D.L., Lawrence, N.A., George, J., Torres, D.T., Lee, A.V. 2006. Decreased lactation capacity and altered milk composition in IRS-1 knockout mice is associated with decreased insulin-dependent phosphorylation of Akt [abstract]. Endocrine Society Meeting. Available: http://www.abstracts2view.com/endo/view.php?nu=ENDO06L_P1-435. Interpretive Summary:
Technical Abstract: Expression of insulin receptor substrates (IRS) 1 and 2 within the mammary gland is both developmentally and hormonally regulated. These proteins were found to be high in mouse mammary tissue at mid-lactation and dramatically decreased with mammary involution. This observation supports the hypothesis that these proteins are induced in the mammary gland with lactogenesis and necessary for normal milk synthesis. To test this hypothesis, expression levels of IRS-1 and 2 were measured in detail during the secretory activation phase of lactogenesis and lactation capacity, along with indices of mammary secretory cell glucose metabolism and cell signaling were compared in normal mice and mice carrying targeted mutations in either IRS-1 or 2. Mammary IRS1 and 2 levels were increased within 1 day of parturition and reached maximal levels by 5 days postpartum. Dams carrying germline mutations of IRS-1, but not IRS-2, displayed reduced lactation capacity (P<0.05). This reduction was associated with decreased mammary gland weight and overall body weight (P<0.05). Milk lactose and water content were modestly decreased in IRS-1 knockout dams (P<0.05). The loss of IRS-1 had little impact on mammary gland expression of milk protein mRNAs, glucose transport, or on the abundance and subcellular localization of Hexokinase II. Loss of IRS-1 did however cause a reduction in insulin-dependent mammary-gland-specific activation of Akt phosphorylation. Interestingly a reduction of insulin-stimulated Akt phosphorylation was noted despite an apparent compensatory increase in insulin-stimulated tyrosine phosphorylation of IRS-2 in the mammary gland. These results support the conclusion that IRS-1 is important to insulin-dependent activation of Akt signaling within the lactating mammary gland, but that loss of this protein has only a modest impact on normal milk synthesis since related signaling proteins such as IRS-2 may act in compensatory fashion.