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Distinct hepatocyte adaptations during gestation and lactation [sheep_SmartSeq3]

ABSTRACT: The liver undergoes adaptive changes during pregnancy and lactation to meet specific physiological demands, but the precise processes, regulatory mechanisms, and functions remain unclear. Using high-resolution single-cell RNA sequencing (scRNA-seq), we comprehensively analyzed hepatocyte adaptations in mice throughout these periods. Our findings revealed a circular trajectory, termed the “pregnancy clock”, during gestation and non-lactating postpartum phases, reverting to the pre-gestation state after recovery. In contrast, lactation induced a distinct branching pathway, characterized by increased fatty acid synthesis and lipid accumulation. Deletion of Gp130 in the JAK/STAT pathway disrupted gestation transitions, leading to delayed embryonic development, while ACSS2 ablation impaired postpartum lipid metabolism, affecting milk quality and offspring growth. Comparative analysis with sheep demonstrated conserved hepatocyte adaptation pathways despite species-specific genetic regulatory networks. These insights offer potential targets for therapeutic interventions to optimize maternal and fetal health and enhance lactation efficiency, with broad implications for reproductive biology and livestock management.

ORGANISM(S): Ovis aries

PROVIDER: GSE272943 | GEO | 2025/09/02

REPOSITORIES: GEO

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Project description:The mammary gland of the lactating mouse synthesizes and secretes milk lipid equivalent to its entire body weight in a single 20 day lactation cycle, making it one of the most active lipid synthetic organs known. To test the hypothesis that multiple metabolic control points and potential regulatory mechanisms are involved in activating lipid and lactose synthesis at the onset of lactation we compared the mammary transcriptome of 130 genes involved in glucose metabolism between late pregnancy and early lactation and in response to dietary fat. We utilized data obtained from microarray analysis of mammary glands from quadruplicate FVB mice at pregnancy day 17, and lactation day 2. Diets containing 8% or 40% lipid were fed from lactation days 5 to 10 and mammary glands and livers of triplicate FVB mice prepared for microarray analysis. We also compared the metabolome obtained from magnetic resonance spectroscopy of flash frozen glands of the mammary gland at day 17 of pregnancy with that at day 2 of lactation. The results provide a global picture of the multiple metabolic strategies utilized to turn a quiescent organ into an incredibly efficient machine for massive but balanced lipid and lactose synthesis and implicate the transcription factor SREBP-1c in regulation of part of the pathway. FVB control time-series mice were on normal lab chow diets and mammary tissue was taken at Pregnant days 12 and 17, plus lactation days 1, 2, and 9 in those animals. the time-points were taken as quadruplicates for each developmental stage. for the dietary component, triplicate FVB dams were fed normal lab chow diets until lactation day 5, when they were converted to diets containing either 8% or 40% Kcal from soy oils (see supplementary table to publication for further detail) for 5 days. At lactation day 10, mammary and liver tissues were taken from these animals and preparred for microarray analysis. All tissues were stabilized for RNA content in RNALater and were then isolated and cleaned up following manufacturer's instructions (Qiagen).

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Distinct hepatocyte adaptations during gestation and lactation [sheep_SmartSeq3]

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