Residual feed intake (RFI) is a measure of feed efficiency, in which low RFI denotes improved feed efficiency. Caloric restriction (CR) is associated with feed efficiency in livestock species and to human health benefits, such as longevity and cancer prevention. We have developed pig lines that differ in RFI, and we are interested in identifying the genes and pathways that underlie feed efficiency. Prepubertal Yorkshire gilts with low RFI (n = 10) or high RFI (n = 10) were fed ad libitum or fed at restricted intake of 80% of maintenance energy requirements for 8 days. We measured serum metabolites and hormones and generated transcriptional profiles of liver and subcutaneous adipose tissue on these animals. Overall, 6,114 genes in fat and 305 genes in liver were differentially expressed (DE) in response to CR, and 311 genes in fat and 147 genes in liver were DE due to RFI differences. Pathway analyses of CR-induced DE genes indicated a dramatic switch to a conservation mode of energy usage by down-regulating lipogenesis and steroidogenesis in both liver and fat. Interestingly, CR altered expression of genes in immune and cell cycle/apoptotic pathways in fat, which may explain part of the CR-driven lifespan enhancement. In silico analysis of transcription factors revealed ESR1 as a putative regulator of the adaptive response to CR, as several targets of ESR1 in our DE fat genes were annotated as cell cycle/apoptosis genes. The lipid metabolic pathway was overrepresented by down-regulated genes due to both CR and low RFI. We propose a common energy conservation mechanism, which may be controlled by PPARA, PPARG, and/or CREB in both CR and feed-efficient pigs.
Transcriptional profiling coupled with blood metabolite analyses were used to identify porcine genes and pathways that respond to a fasting treatment or to a D298N missense mutation in the melanocortin-4 receptor (MC4R) gene. Gilts (12 homozygous for D298 and 12 homozygous for N298) were either fed ad libitum or fasted for 3 days. Fasting decreased body weight, backfat, and serum urea concentration and increased serum nonesterified fatty acid. In response to fasting, 7,029 genes in fat and 1,831 genes in liver were differentially expressed (DE). MC4R genotype did not significantly affect gene expression, body weight, backfat depth, or any measured serum metabolite concentration. Pathway analyses of fasting-induced DE genes indicated that lipid and steroid synthesis was downregulated in both liver and fat. Fasting increased expression of genes involved in glucose sparing pathways, such as oxidation of amino acids and fatty acids in liver, and in extracellular matrix pathways, such as cell adhesion and adherens junction in fat. Additionally, we identified DE transcription factors (TF) that regulate many DE genes. This confirms the involvement of TF, such as PPARG, SREBF1, and CEBPA, which are known to regulate the fasting response, and implicates additional TF, such as ESR1. Interestingly, ESR1 controls several fasting induced genes in fat that are involved in cell matrix morphogenesis. Our findings indicate a transcriptional response to fasting in two key metabolic tissues of pigs, which was corroborated by changes in blood metabolites, and the involvement of novel putative transcriptional regulators in the immediate adaptive response to fasting.
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