Microarray gene expression profiles of fasting induced changes in liver and adipose tissues of pigs expressing the melanocortin-4 receptor D298N variant

Authors: LKHAGVADORY, SENDER - IOWA STATE UNIV.; QU, LONG - IOWA STATE UNIV.; CAI, WEIGUO - IOWA STATE UNIV.; COUTURE, LOIVER - IOWA STATE UNIV.; Barb, Claude; Hausman, Gary; REKAYA, ROMDHANE - UGA; NETTLETON, DAN - IOWA STATE UNIV.; ANDERSON, LLOYD - IOWA STATE UNIV.; DEKKERS, JACK - IOWA STATE UNIV.; TUGGLE, CHRIS - IOWA STATE UNIV.

Submitted to: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/9/2009
Publication Date: 6/10/2009
Citation: Lkhagvadory, S., Qu, L., Cai, W., Couture, L., Barb, C.R., Hausman, G.J., Rekaya, R., Nettleton, D., Anderson, L., Dekkers, J., Tuggle, C. 2009. Microarray gene expression profiles of fasting induced changes in liver and adipose tissues of pigs expressing the melanocortin-4 receptor D298N variant. Physiological Genomics. 38(1)98-111.

Interpretive Summary: Efficient use of this feed by the pigs to produce live weight is important to swine producers. Selection for feed efficiency has been relatively unsuccessful at changing feed efficiency. Selection for lean growth rate has been shown to improve feed efficiency and has been used by many pig breeding companies. As pigs are approaching optimum levels of lean, new methods for improving feed efficiency are needed. A class of receptors, melanocortin-3 and 4-receptor (MC3/4), are located within the brain and modulate feed intake in rodents. Stimulation of the receptor (agonist) inhibits feed intake where as blockade (antagonist) of the receptor increases intake. Our knowledge of factors regulating voluntary feed intake in humans and domestic animals is very limited. Previous reports demonstrated that growth rate and feed intake are related to expression of a mutation of the melanocortin-4-receptor (MC4R) gene in pigs. Pigs were subjected to an acute fast to identify genes and pathways that respond to fast in pigs with alternate genotypes at MC4R gene in liver and adipose tissue. Pathway gene analyses indicate that both tissues down-regulated energetically costly biosynthetic processes such as lipid/steroid synthesis and switched to energy conservation and efficient utilization pathways. These results will provide an understanding of the underlying genetic and physiological basis of feed intake and efficiency, and will suggest specific genes to target for genetic improvement through marker-assisted selection.

Technical Abstract: Transcriptional profiling was used to identify porcine genes and pathways that respond to a fasting in pigs that express the missense mutation (D298N) in the melanocortin-4 receptor (MC4R) gene, which has been associated with increased growth and feed efficiency. Prepubertal gilts (n=24; 12 wildtype and 12 homozygous for D298N MC4R) were either fed ad lib. or fasted for 3 days in a completely randomized block design with 2x2 factorial treatment structure. The Affymetrix Porcine Genome Genechip was used to profile gene expression in RNA from liver and subcutaneous fat. Due to fasting, 7,029 genes in adipose tissue and 1,831 genes in liver were declared differentially expressed (q<0.05), but an effect of MC4R was not observed on expression in either tissues under same criterion. Pathway analyses of their patterns indicate that both tissues down-regulated energetically costly biosynthetic processes such as lipid/steroid synthesis and switched to energy conservation and efficient utilization pathways. Fasting increased expression of liver genes involved in fatty acid oxidation, gluconeogenesis, and cell cycle arrest. In fat, fasting induced cell-to-cell communication and adipocytokine signaling pathways. An analysis of key transcription factors known to target fasting induced genes confirms the involvement of previously known transcription factors such as PPAR-gama, PPAR-alpha, C/EBP-alpha, SREBF1 but also implicate the importance of additional transcription factors that have not been reported to be involved in homeostatic responses such as estrogen receptor 1 (ESR1). Furthermore, we propose that fasting induced genes involved in cell matrix changes in fat are controlled by ESR1. These findings have identified novel transcriptional genes that response to fasting in key metabolic tissues and are associated with blood metabolite data; thus it is propose that theses changes in transcriptional gene expression represents a fasting adaptive response to fast.