Homeorhetic adaptation to lactation: comparative transcriptome analysis of mammary, liver, and adipose tissue during the transition from pregnancy to lactation in rats

Abstract

Tissue-specific shifts in a dam's metabolism to support fetal and neonatal growth during pregnancy and lactation are controlled by differential expression of regulatory genes. The goal of this study was to identify a more detailed cohort of genes in mammary, liver, and adipose tissue that are transcriptionally controlled during the pregnancy to lactation evolution and explore the relationship of these genes to core clock genes. Total RNA was isolated from mammary, liver and adipose tissues collected from rat dams on day 20 of pregnancy (P20) and day 1 of lactation (L1) and gene expression was measured using Rat 230 2.0 Affymetrix GeneChips. Gene functional analysis revealed that pathway associated metabolism (carbohydrate, amino acid, lipid, cholesterol, protein) were enriched (P < 0.001) in the mammary gland during P20 to L1 transition. Approximately 50% of the genes associated with solute transport, as well as lipogenesis were up-regulated in the mammary gland during P20 to L1 transition compared to 10% in liver and 15% in adipose tissue. Genes engaged in conveying glucose (INSR, GLUT1, GLUT4, SGLT1, and SGLT2), bicarbonate (SLC4), sodium (SLC9), zinc (SLC30), copper (SLC31), iron (SLC40) in tandem with rate-limiting lipogenic genes (ACACA, FASN, PRLR, SREBP2, THRSP) were specifically enriched in the mammary gland during the P20 to L1 evolution. Our results provide insight into a cross-tissue transcriptional repertoire that is associated with homeorhetic adaptation needed to support lactation, and at the onset of lactation the mammary gland becomes a factory for macromolecular biosynthesis through inducing genes participating in nutrient transfer and lipid biosynthesis.

LACTATION BIOLOGY SYMPOSIUM: Circadian clocks as mediators of the homeorhetic response to lactation1

“…Because lactation represents the continuum of reproduction in mammals, it is possible the circadian system plays a role in timing the coordinated changes in hormonal milieu and metabolism needed to initiate lactation. Our finding that changes in molecular clocks occur in multiple tissues during the transition from pregnancy to lactation supports this hypothesis (Gasey et al, 2009;Patel et al, 2011), as well as the fact that clock/clock mutant mice cannot adequately nourish neonates during lactation (Dolatshad et al, 2006). Further, because core molecular clocks regulate important rate-limiting processes important to the function of organs, changes in peripheral clocks during the transition from pregnancy to lactation are likely to play a key role in changing the metabolome of the dam during the periparturient period to support milk synthesis.…”

“…We used rats as models to study homeorhetic regulation during the periparturient period and collected mammary, liver, and adipose tissues from dams on d 20 and 21 of pregnancy, during prelabor, labor, and at birth, and on d 1 and 3 of lactation (for details, see Plaut et al, 1999;Ronca et al, 2003;Lintault et al, 2007;Gasey et al, 2009;Patel et al, 2011). Lipid synthetic capacity for all 3 tissues was determined by measuring the rate of incorporation of uniformly labeled '""G-glucose into lipids.…”

“…Global transcriptional analysis was used to investigate how gene expression changed across multiple tissues during the transition from pregnancy to lactation (Gasey et al, 2009;Patel et al, 2011). Total RNA was isolated from mammary, liver, and adipose tissues from rat dams on pregnancy d 20 and lactation d 1, and Affymetrix gene chips were used to measure gene expression.…”

“…Total RNA was isolated from mammary, liver, and adipose tissues from rat dams on pregnancy d 20 and lactation d 1, and Affymetrix gene chips were used to measure gene expression. We found that genes changing expression from late pregnancy to the onset of lactation enriched multiple pathways and gene ontologies related to energy homeostasis as well as gene sets classically associated with central nervous system reception and integration (Gasey et al, 2009;Patel et al, 2011).…”

Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy

“…PHACTR1, LPL, SMAD3, ABO and SLC22A5 may contribute to reproductive timing (menarche, menopause) in women [57][58][59] and animals [60]. Expression of PHACTR1 [61], KCNK5 [62], MRAS and ADAMST7 [63] appear to regulate lactation capacity. Some gene deficiencies also cause pregnancy loss (e.g.…”