Gene expression in hypothalamus, liver, and adipose tissues and food intake response to melanocortin-4 receptor agonist in pigs expressing melanocortin-4 receptor mutations

Abstract

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.

Development of Optimal Breeding Pigs Using DNA Marker Information

“…The PRKAG3 AA animals also had less drip loss, which means higher water-holding capacity. Our results are consistent with previous reports in which the AA genotype pigs had Unfortunately, we did not have the backfat thickness records to test if the MC4R D298N polymorphism was associated with fat deposition traits in KNP x YS F2 animals, but it warrants the identification of the MC4R gene structure in KNP pigs to investigate the functional mechanisms of obesity-related phenotypes (Barb et al, 2010;Switonski et al, 2010). The CAST RsaI polymorphism was associated with moisture and crude protein levels (Table 4).…”

Role of Adipose Secreted Factors and Kisspeptin in the Metabolic Control of Gonadotropin Secretion and Puberty

“…Factors secreted by adipose tissue or "adipokines" continue to be discovered and are linked to important physiological roles (Ahima, 2006) including the innate immune response (Schäffler & Schöolmerich, 2010). In a number of recent experiments transcriptional profiling demonstrated that 5,000 to 8,000 adipose tissue genes were differentially expressed during central stimulation of the melanocortin 4 receptor (Barb et al, 2010a) and several conditions such as fasting (Lkhagvadorj et al, 2009) and feed restriction . In contrast, 300 to 1,800 genes were differentially expressed in livers in these three studies (Barb et al, 2010a;Lkhagvadorj et al, 2009Lkhagvadorj et al, , 2010.…”

“…In a number of recent experiments transcriptional profiling demonstrated that 5,000 to 8,000 adipose tissue genes were differentially expressed during central stimulation of the melanocortin 4 receptor (Barb et al, 2010a) and several conditions such as fasting (Lkhagvadorj et al, 2009) and feed restriction . In contrast, 300 to 1,800 genes were differentially expressed in livers in these three studies (Barb et al, 2010a;Lkhagvadorj et al, 2009Lkhagvadorj et al, , 2010. This degree of differential gene expression in adipose depots reflects the potential influence of adipose tissue as a secretory organ on multiple systems in the body.…”

“…Abbreviations: ADIPOR2 = adiponectin receptor 2, AGTR1 = angeotensin II receptor, ANG = angiotensin, ANGPTL = angiopoietin-like protein, APO = apolipoprotein, BDNF = brain-derived neurotrophic factor, bFGF = basic fibroblast growth factor, BMP = bone morphogenic protein, BMPR2 = bone morphogenic protein receptor 2, CIQTN4 = complement-c1q tumor necrosis factor-related protein 4, CNTF = ciliary neurotrophic factor, CTGF = connective tissue growth factor, CTRP4 = complement-c1q tumor necrosis factor-related protein 4, EDNRB = endothelin receptor type B, EGFR = epidermal growth factor receptor, ESR1 = estrogen receptor 1, GNRHR2 = gonadotropin-releasing hormone receptor 2, IFNG = interferon gamma, IGF = insulin-like growth factor, IGF-IR = IGF-I receptor, IGFBP = insulin-like growth factor binding protein, IL = interleukin, INSR = insulin receptor, LDLR = low density lipoprotein receptor, LHCGR = luteinizing hormone-choriogonadotropin receptor, LPL = lipoprotein lipase, MCP-1 = monocyte chemoattractant protein-1, NGFR = nerve growth factor receptor, NPY = neuropeptide Y, OB-rb = long form leptin receptor, NUCB2 = nucleobindin 2, PAI-1 = plasminogen activator inhibitor-1, PDGFD = platelet derived growth factor D, PGRMC1 = progesterone receptor membrane component 1, RANTES = chemokine (c-c motif) ligand 5, RBP = retinol binding protein, RLN = relaxin, TGF = transforming growth factor, RTN = reticulon, THR = thyroid hormone receptor, TLR = toll-like receptor, TNF = tumor necrosis factor, TSHR = thyroid-stimulating hormone receptor, VEGFC = vascular endothelial growth factor C. References: Barb et al, 2010a;Basu et al, 2012;Chen et al, 2005;Hausman & Hausman, 2004;Hausman et al, 2009;Lehr et al, 2012;Lim et al, 2008;Lkhagvadorj et al, 2009Lkhagvadorj et al, , 2010Renes et al, 2009;Zhong et al, 2010 intake and body weight in mice by reducing expression of NPY in the hypothalamus via a malonyl-Coenzyme A mechanism, which supports the idea that lipid metabolism in the CNS plays a role in the control of appetite (Loftus et al, 2000). Furthermore, long-chain Furthermore, long-chain fatty acyl CoAs (LC-CoAs), such as oleyl-CoA, can activate ATP-sensitive K + channels in non-neuronal cells (Larsson et al, 1996).…”

“…administration of leptin failed to stimulate LH secretion in the well-fed intact prepubertal gilt (Barb et al, 2004). Obviously, hypothalamic explants are deprived of neuroanatomical connections with other extra-hypothalamic tissues that may convey the heightened negative feedback action of estradiol on the GnRH pulse generator that occurs during pubertal development (Barb et al, 2010a), which may in part explain the failure of a LH response to i.c.v. administration of leptin in the pig.…”