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Transcriptome analyses of liver in newly-hatched chicks during the metabolic perturbation of fasting and re-feeding reveals THRSPA as the key lipogenic transcription factor.

ABSTRACT: BACKGROUND:The fasting-refeeding perturbation has been used extensively to reveal specific genes and metabolic pathways that control energy metabolism in the chicken. Most global transcriptional scans of the fasting-refeeding response in liver have focused on juvenile chickens that were 1, 2 or 4?weeks old. The present study was aimed at the immediate post-hatch period, in which newly-hatched chicks were subjected to fasting for 4, 24 or 48?h, then refed for 4, 24 or 48?h, and compared with a fully-fed control group at each age (D1-D4). RESULTS:Visual analysis of hepatic gene expression profiles using hierarchical and K-means clustering showed two distinct patterns, genes with higher expression during fasting and depressed expression upon refeeding and those with an opposing pattern of expression, which exhibit very low expression during fasting and more abundant expression with refeeding. Differentially-expressed genes (DEGs), identified from five prominent pair-wise contrasts of fed, fasted and refed conditions, were subjected to Ingenuity Pathway Analysis. This enabled mapping of analysis-ready (AR)-DEGs to canonical and metabolic pathways controlled by distinct gene interaction networks. The largest number of hepatic DEGs was identified by two contrasts: D2FED48h/D2FAST48h (968 genes) and D2FAST48h/D3REFED24h (1198 genes). The major genes acutely depressed by fasting and elevated upon refeeding included ANGTPL, ATPCL, DIO2, FASN, ME1, SCD, PPARG, SREBP2 and THRSPA-a primary lipogenic transcription factor. In contrast, major lipolytic genes were up-regulated by fasting or down-regulated after refeeding, including ALDOB, IL-15, LDHB, LPIN2, NFE2L2, NR3C1, NR0B1, PANK1, PPARA, SERTAD2 and UPP2. CONCLUSIONS:Transcriptional profiling of liver during fasting/re-feeding of newly-hatched chicks revealed several highly-expressed upstream regulators, which enable the metabolic switch from fasted (lipolytic/gluconeogenic) to fed or refed (lipogenic/thermogenic) states. This rapid homeorhetic shift of whole-body metabolism from a catabolic-fasting state to an anabolic-fed state appears precisely orchestrated by a small number of ligand-activated transcription factors that provide either a fasting-lipolytic state (PPARA, NR3C1, NFE2L2, SERTAD2, FOX01, NR0B1, RXR) or a fully-fed and refed lipogenic/thermogenic state (THRSPA, SREBF2, PPARG, PPARD, JUN, ATF3, CTNNB1). THRSPA has emerged as the key transcriptional regulator that drives lipogenesis and thermogenesis in hatchling chicks, as shown here in fed and re-fed states.

SUBMITTER: Cogburn LA

PROVIDER: S-EPMC6995218 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Transcriptome analyses of liver in newly-hatched chicks during the metabolic perturbation of fasting and re-feeding reveals THRSPA as the key lipogenic transcription factor.

Cogburn Larry A LA Trakooljul Nares N Wang Xiaofei X Ellestad Laura E LE Porter Tom E TE

BMC genomics 20200131 1

<h4>Background</h4>The fasting-refeeding perturbation has been used extensively to reveal specific genes and metabolic pathways that control energy metabolism in the chicken. Most global transcriptional scans of the fasting-refeeding response in liver have focused on juvenile chickens that were 1, 2 or 4 weeks old. The present study was aimed at the immediate post-hatch period, in which newly-hatched chicks were subjected to fasting for 4, 24 or 48 h, then refed for 4, 24 or 48 h, and compared w ...[more]

PMID: 32005146

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Project description:BackgroundThe hypothalamus plays a central role in regulating appetite and metabolism. However, the gene networks within the hypothalamus that regulate feed intake and metabolism, and the effects of fasting on those pathways are not completely understood in any species. The present experiment evaluated global hypothalamic gene expression in newly hatched chicks using microarray analysis to elucidate genes and pathways regulated by feeding, fasting, and delayed feeding. Ten groups of chicks were sampled over four days post-hatch, including fed, fasted, and 48 h fasted followed by access to feed for 4 h, 24 h, and 48 h. Hypothalamic samples were collected for microarray analysis (n = 4). Expression patterns of selected genes were confirmed by quantitative real-time PCR. Pathway analysis of the microarray results predicted a network of genes involved in neuropeptide or neurotransmitter signaling. To confirm the functionality of this predicted gene network, hypothalamic neurons from fed and fasted chicks were isolated and cultured in the presence of neuropeptide Y, somatostatin, alpha-melanocyte stimulating hormone, norepinephrine, and L-phospho-serine. Results confirmed functional relationships among members of the predicted gene network. Moreover, the effects observed were dependent upon the nutritional state of the animals (fed vs. fasted).ResultsDifferences in gene expression (> or = 1.6 fold) were detected in 1,272 genes between treatments, and of those, 119 genes were significantly (P < 0.05) different. Pathway Miner analysis revealed that six genes (SSTR5, NPY5R, POMC, ADRB2, GRM8, and RLN3) were associated within a gene network. In vitro experiments with primary hypothalamic neurons confirmed that receptor agonists involved in this network regulated expression of other genes in the predicted network, and this regulation within the network was influenced by the nutritional status and age of the chick.ConclusionsMicroarray analysis of the hypothalamus during different nutritional states revealed that many genes are differentially regulated. We found that functional interactions exist among six differentially regulated genes associated within a putative gene network from this experiment. Considering that POMC, an important gene in controlling metabolism, was central to this network, this gene network may play an important role in regulation of feeding and metabolism in birds.

Project description:This study integrates global transcriptional profiling and the metabolic perturbation induced by fasting and re-feeding. Genetic control of growth and development should be revealed by systematic modeling of metabolic and regulatory pathways. Chicken oligo arrays were used for transcriptional profiling in two time-course experiments. Two critical developmental stages were chosen: immediately after hatchling (Wk1) and prior to marketing of broiler chickens (Wk6). Only male chickens were used to simplify the experimental design. A RNA reference design was employed for microarray hybridization using two reference RNA pools derived from all individuals sampled at either Wk1 or Wk6. Microarray data was acquired using GenePix Pro software. Loess normalization and a linear mixed model were applied in data processing using the R statistical package with LIMMA software [Smyth, G. K. (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Statistical Applications in Genetics and Molecular Biology, Vol. 3, No. 1, Article 3]. The results show hundreds of differentially expressed genes, which are regulated by age and the metabolic perturbation of fasting and re-feeding. Numerous common genes were found at both developmental stages (Wk1 and Wk6) that could be candidates for controlling growth and development of chickens. Differential expression revealed by either microarray or qRT-PCR analyses of selected genes was highly consistent. QRT-PCR verification of genes acutely depressed by fasting includes AGO1, ANGTPL3, ATPCL, FASN, FAT, ME1, PPARG, SCD1, SREBP1 and THRSPA. Genes up-regulated by fasting were ALDOB, IL-15, LDHB, LIPIN2, PANK1, PPARA and UPP2. These genes are functionally assigned to metabolic enzymes, transcription factors, acute phase proteins, immune factors and involved in various pathways (i.e., fatty acid and amino acid metabolism, glycolysis, growth factor signaling and immune defense). Keywords: Hepatic transcripts, oligo-array, chicken, metabolic perturbation, fasting and re-feeding

Dataset Information

Transcriptome analyses of liver in newly-hatched chicks during the metabolic perturbation of fasting and re-feeding reveals THRSPA as the key lipogenic transcription factor.

Publications

Transcriptome analyses of liver in newly-hatched chicks during the metabolic perturbation of fasting and re-feeding reveals THRSPA as the key lipogenic transcription factor.

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