Gene expression in hypothalamus, liver, and adipose tissues and food intake response to melanocortin-4 receptor agonist in pigs expressing melanocortin-4 receptor mutations.
Transcriptional profiling was used to identify genes and pathways that responded to intracerebroventricular injection of melanocortin-4 receptor (MC4R) agonist [Nle(4), d-Phe(7)]-α-melanocyte stimulating hormone (NDP-MSH) in pigs homozygous for the missense mutation in the MC4R, D298 allele (n = 12), N298 allele (n = 12), or heterozygous (n = 12). Food intake (FI) was measured at 12 and 24 h after treatment. All pigs were killed at 24 h after treatment, and hypothalamus, liver, and back-fat tissue was collected. NDP-MSH suppressed (P < 0.004) FI at 12 and 24 h in all animals after treatment. In response to NDP-MSH, 278 genes in hypothalamus (q ≤ 0.07, P ≤ 0.001), 249 genes in liver (q ≤ 0.07, P ≤ 0.001), and 5,066 genes in fat (q ≤ 0.07, P ≤ 0.015) were differentially expressed. Pathway analysis of NDP-MSH-induced differentially expressed genes indicated that genes involved in cell communication, nucleotide metabolism, and signal transduction were prominently downregulated in the hypothalamus. In both liver and adipose tissue, energy-intensive biosynthetic and catabolic processes were downregulated in response to NDP-MSH. This included genes encoding for biosynthetic pathways such as steroid and lipid biosynthesis, fatty acid synthesis, and amino acid synthesis. Genes involved in direct energy-generating processes, such as oxidative phosphorylation, electron transport, and ATP synthesis, were upregulated, whereas TCA-associated genes were prominently downregulated in NDP-MSH-treated pigs. Our data also indicate a metabolic switch toward energy conservation since genes involved in energy-intensive biosynthetic and catabolic processes were downregulated in NDP-MSH-treated pigs.
Barb
C Richard
CR
Poultry Processing and Swine Physiology Research, Agricultural Research Service, United States Department of Agriculture;
Hausman
Gary J
GJ
Rekaya
Romdhane
R
Lents
Clay A
CA
Lkhagvadorj
Sender
S
Qu
L
L
Cai
W
W
Couture
Oliver P
OP
Anderson
Lloyd L
LL
Dekkers
Jack C M
JC
Tuggle
Christopher K
CK
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D004435:Eating / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006720:Homozygote; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000235:genetics*; D015203:Reproducibility of Results; D034421:Sus scrofa / Q000235:genetics*; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D003576:Electron Transport Complex IV