Laporta J, Rosa GJM, Naya H, Carriquiry M. Liver functional genomics in beef cows on grazing systems: novel genes and pathways revealed. Physiol Genomics 46: 138 -147, 2014. First published December 10, 2013; doi:10.1152/physiolgenomics.00120.2013.-The adaptation of the liver to periods of negative energy balance is largely unknown in beef cattle on grazing systems. We evaluated liver transcriptome throughout gestation and early lactation of purebred and crossbred beef cows [Angus, Hereford, and their F1 crossbreeds (CR)], grazing high or low herbage allowances (HA) of native grasslands (4 and 2.5 kg dry matter/kg body wt annual mean; n ϭ 16) using an Agilent 4 ϫ 44k bovine array. A total of 4,661 transcripts were affected by days [272 Ն2.5-fold difference, false discovery rate (FDR) Յ 0.10] and 47 pathways were altered during winter gestation (Ϫ165 to Ϫ15 days relative to calving), when cows experienced decreased body condition score, decreased insulin, and increased nonesterified fatty acid concentrations. Gluconeogenesis and fatty acid oxidation pathways were upregulated, while cell growth, DNA replication, and transcription pathways were downregulated (FDR Յ 0.25). We observed only small changes in the liver transcriptome during early lactation (ϩ15 to ϩ60 days). A total of 225 genes were differentially expressed (47 Ն2-fold difference, FDR Յ 0.10) between HA. The majority of those were related to glucose and pyruvate metabolism and were upregulated in high HA, reflecting their better metabolic status. Two genes were upregulated in CR cows, but 148 transcripts (74 Ն2-fold change difference, FDR Յ 0.10) were affected by the HA and cow genotype interaction. The transcriptional changes observed indicated a complex and previously unrecognized, hepatic adaptive program of grazing beef cows in different nutritional environments. Novel target candidate genes, metabolic pathways, and regulatory mechanisms were reported. beef cattle; rangelands; energy balance; hepatic mRNA; microarrays THE LIVER IS THE MAJOR METABOLICALLY active organ in mammals. Pregnancy and lactation are physiological stages during which alterations in hepatic metabolism are expected because of a greater demand for nutrients and metabolites by the fetus and mammary gland, respectively (4, 29). Extensive beef cow-calf production systems depend on the quantity and quality of grazed forages to meet their nutritional demands throughout the year. In temperate environments, nutrient availability of grazed forages fluctuates during seasons (13, 42), and often, in spring-calved beef cows, the lowest nutrient availability occurs during pregnancy in winter, and cows lose body tissue to support conceptus growth (13,37,42).Microarray technology has been used to evaluate hepatic metabolic adaptations to pregnancy (19), transition period, early and midlactation (1, 25, 28), negative energy balance (NEB) or dietary restriction (1,26,29), and transition-related metabolic diseases (27) in dairy cows. In is well known that dairy and beef cows have been selected fo...