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Transcriptomic responses of the liver and adipose tissues to altered carbohydrate-fat ratio in diet: an isoenergetic study in young rats
© The Author(s) 2017
Received: 22 June 2016
Accepted: 1 March 2017
Published: 8 April 2017
To elucidate the effects of altered dietary carbohydrate and fat balance on liver and adipose tissue transcriptomes, 3-week-old rats were fed three kinds of diets: low-, moderate-, and high-fat diets (L, M, and H) containing a different ratio of carbohydrate-fat (C-F) (65:15, 60:20, and 35:45 in energy percent, respectively).
The rats consumed the diets for 9 weeks and were subjected to biochemical and DNA microarray analyses.
The rats in the H-group exhibited lower serum triacylglycerol (TG) levels but higher liver TG and cholesterol content than rats in the L-group. The analysis of differentially expressed genes (DEGs) between each group (L vs M, M vs H, and L vs H) in the liver revealed about 35% of L vs H DEGs that were regulated in the same way as M vs H DEGs, and most of the others were L- vs H-specific. Gene ontology analysis of these L vs H DEGs indicated that those related to fatty acid synthesis and circadian rhythm were enriched. Interestingly, about 30% of L vs M DEGs were regulated in a reverse way compared with L vs H and M vs H DEGs. These reversed liver DEGs included M-up/H-down genes (Sds for gluconeogenesis from amino acids) and M-down/H-up genes (Gpd2 for gluconeogenesis from glycerol, Agpat9 for TG synthesis, and Acot1 for beta-oxidation). We also analyzed L vs H DEGs in white (WAT) and brown (BAT) adipose tissues and found that both oxidation and synthesis of fatty acids were inhibited in these tissues.
These results indicate that the alteration of dietary C-F balance differentially affects the transcriptomes of metabolizing and energy-storing tissues.
Availability of body carbohydrate (C) and fat (F) for energy production varies depending on the animal’s circumstances. Fat is mainly consumed during resting conditions at about 90% of total energy; however, this ratio can be rapidly decreased to nearly 10% through acute bouts of exercise and substituted by the energy supply from aerobic or anaerobic respiration of C [7, 38]. Under fasting conditions, carbohydrate is depleted within a day, and about four fifths of basal metabolic rate is maintained by fat and the rest by amino acids for several days . These metabolic switches of energy source between C and F are more interchangeable than protein (P) or amino acids because of the metabolic linkage mediated by the key organic substances: glycerol-3-phosphate both as the product of triacylglycerol (TG) hydrolysis and as the substrate for gluconeogenesis, NADP(H) both as the hydrogen acceptor of the pentose phosphate pathway and as the hydrogen donor for fatty acid (FA) synthesis, and acetyl-CoA as the activated substrate of the TCA cycle and of FA synthesis. Thus, dietary C to F ratio (C-F ratio) has a considerable effect on the energy homeostasis of animals.
Generally, experimental rodents accept diets composed of energetic C-F ranging from 50:30 to 70:10 to provide a constant energy ratio of 20% P . In rodents, AIN93G (C:F:P = 64:16:20) during rapid growth, pregnancy, and lactation and AIN93M (C:F:P = 76:9:15) during maintenance were often used for standard diets . Keeping this P energy ratio over 15% is critical for normal growth of adolescent animals [13, 23, 29]. But effects of an altered C-F on metabolic parameters differ depending on dietary fat species such as soybean and corn oils of plant origin, and beef tallow and lard of animal origin. It was shown that a high-fat diet (HFD, C:F:P = 30:40:20) made of lard was more deleterious to insulin resistance and hepatic steatosis than an HFD made of soybean oil in comparison with a low-fat diet (LFD, C:F:P = 14:64:22) [45, 50]. Deol et al. reported that an HFD (C:F:P = 43:40:16) containing soybean oil and hydrogenated coconut oil at 1:1 ratio was more obesogenic than an HFD mainly containing hydrogenated coconut oil . These differences were considered to be caused by the lipid composition of the dietary fat [1, 8, 12, 17, 32, 34]. Polyunsaturated FAs (PUFAs) are the main contributors to the physiological activity of dietary fat; soybean oil contains 15% saturated FAs and 55% PUFAs, while lard contains 40% saturated FAs and 10% PUFAs. Duivenvoorde et al. showed that an HFD with predominantly saturated FAs increased ectopic fat storage, liver damage, and adipocyte size as compared to an HFD with predominantly PUFAs and reduced response flexibility to fast re-feeding and oxygen restriction . Especially, eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) were reported to reduce insulin resistance and hepatic steatosis [26, 31]. Though small in percentage, sterols are critical factors for animal lipid homeostasis; the soybean oil used in our study contained 0.0024% cholesterol and 0.33% phytosterols, while the lard contained 0.086% cholesterol and no phytosterols. Specifically, phytosterols have been shown to exert beneficial effects on lipid homeostasis under metabolically stressed conditions such as an HFD containing predominantly saturated FAs [5, 6, 16, 27, 36]. However, there are few studies on the transcriptomic effects of a gradual change in the C-F under more moderate conditions, such as the use of diets containing natural plant oils or restricted feeding [30, 37]. In the present study, we conducted an isoenergetic study using a soybean oil-rich diet and found fewer deleterious effects on tissue metabolism but a drastic change in the tissue transcriptome.
Three-week-old male Wistar rats (Charles River Laboratories Japan, Kanagawa, Japan) were housed in a temperature- and humidity-controlled room with a 12-h light-dark cycle (light 06:30–18:30, dark 18:30–06:30). All animal experimental protocols were approved by the Animal Use Committee of the Takasaki University of Health and Welfare.
The rats were acclimated to the laboratory environment for a week with chow diets (MF, Oriental yeast, Tokyo, Japan). The animals were divided into three groups so that the average body weights of each group were equal to each other before being given diets with different C-F energy ratios: low (L) 65:15, moderate (M) 60:20, and high (H) 35:45 fat diet groups. The rats were fed diets ad libitum for a week. Then, the L-group was fed ad libitum and the other groups were fed isoenergetically compared with the L-group for 9 weeks. The diets were purchased from Research Diets, Inc. (New Brunswick, NJ, USA). Detailed compositions of each diet are shown in Additional file 1. Diets were removed 17 h before dissection, and the rats were sacrificed to collect the blood, liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Because an obviously decreased dietary intake was observed for two rats belonging to the M- or H-groups (M_7 and H_11 in identical number), the use of these two rats were not included in all analyses to achieve consistency in the isoenergetic study (n = 4–5 in each group). Serum and plasma were extracted using standard methods and separated from whole blood. Small hepatic pieces were immersed into RNAlater (Qiagen, Tokyo, Japan). The rest hepatic pieces, WAT, and BAT were frozen immediately after extirpation using liquid nitrogen. All samples were stored at −80 or −150 °C until analysis.
Measurement of blood biochemical parameters
Measurement of hepatic lipids
Hepatic lipids were extracted according to a previous method . Briefly, 100 mg of frozen hepatic pieces were homogenized in 2 mL of cooled chloroform-methanol solution (2:1) using a multibead shocker (Yasui Kikai Corporation, Osaka, Japan). Filtered samples were adjusted to 4 mL with chloroform-methanol solution and were washed with 0.8 mL of purified water. Subsequent washes were performed by adding 3.75 mL of chloroform-methanol-water solution (2:1:0.75), and the resulting extracts were dried by evaporation. Extracted lipids were resolved with 1 mL of isopropanol.
Hepatic TG, total cholesterol, and total bile acids were measured using Cholestest TG, Cholestest CHO (Sekisui Medical, Tokyo, Japan), and total bile acids assay kits (Diazyme Laboratories, Poway, CA, USA), respectively.
DNA microarray assay
Total RNA was isolated from each immersed hepatic piece, WAT, and BAT by TRIzol reagent (Invitrogen Japan, Tokyo, Japan) and purified using RNeasy mini kits (Qiagen). Anti-sense RNA was synthesized from 100 or 200 ng of purified total RNA, and biotinylated complementary RNA (cRNA) was obtained using a GeneChip 3’IVT Express Kit (Affymetrix, Santa Clara, CA, USA). The cRNA was fragmented and hybridized to a GeneChip Rat Genome 230 2.0 Array (Affymetrix) for 16 h at 45 °C. The arrays were washed and stained with phycoerythrin using the GeneChip Fluidics Station 450 (Affymetrix) and submitted to scanning on an Affymetrix GeneChip Scanner 3000 7G. The Affymetrix GeneChip Command Console Software was used to make CEL files.
DNA microarray data analysis
The CEL files derived from the liver, WAT, and BAT were quantified using robust multi-array average (RMA), factor analysis for robust microarray summarization (quantile normalization, qFARMS), and GCRMA, respectively [19, 22, 46], using the statistical language R (2.7.1) (http://www.r-project.org/) (R ), and Bioconductor (2.2) (http://www.bioconductor.org/) . Hierarchical clustering was performed using the pvclust function in R . The rank products (RP) method was used to identify differentially expressed gene probe sets of the quantified data . The probe sets with a false discovery rate (FDR) <0.05 were considered to be differentially expressed between each group (L vs M, M vs H, and L vs H).
The up- and downregulated probe sets picked out at FDR < 0.05 were functionally classified by the Biological Process in Gene Ontology (GO) with the Functional Annotation Tool of the Database for Annotation, Visualization, and Integrated Discovery (DAVID) [9, 21] and Quick GO (http://www.ebi.ac.uk/QuickGO/) . In analysis of the liver, EASE scores, which are modified Fisher’s exact test p values were used to extract statistically overrepresented GO terms, and GO terms with p values <0.01 were regarded as significantly enriched. In analysis of WAT and BAT, Benjamini-Hochberg correction p values were used to extract statistically overrepresented GO terms, and GO terms with p values <0.05 were regarded as significantly enriched.
Predicted upstream regulators among liver and adipose tissue transcriptomes were analyzed using Qiagen’s Ingenuity Pathway Analysis (IPA, Qiagen, https://www.qiagenbioinformatics.com/products/ingenuity-pathway-analysis/). Activation z-scores were calculated as a measure of upstream regulators analysis. An absolute z-score ≥2.5 was judged as significantly activated or inhibited. Common upstream regulators that were predicted to be activated or inhibited in the liver, WAT, and BAT were picked out from a list of all upstream regulators.
The results are shown as the means ± SDs. One-way ANOVA was used to assess the differences among three groups, and Tukey-Kramer comparison was used for pairwise comparisons between multiple groups. Differences at p ≤ 0.05 were considered to be significant.
Characterization of hepatic genes affected by the altered balance of carbohydrate and fat in the diet
Rats were fed three kinds of diets containing different ratios of C-F in constant total energy (L, M, and H, Additional file 1). In our preliminary experiment of feeding ad libitum, energy intakes (Kcal/g-BW) were almost the same among the three groups from week 2 to week 4. Therefore, rats were pair-fed to keep by isoenergetic conditions, and dietary restriction derived from pair-feeding has not been occurred. During the experimental period of 9 weeks, the rats in each group showed no between-group differences in body weight (Additional file 2a, b). Also, the liver and the WAT weights showed no differences among groups (Additional file 2b). Biochemical analysis of the blood revealed differences in several markers among experimental groups (Table 1). The H-group showed higher levels of alanine aminotransferase (ALT) and lower levels of TG, phospholipid, and HDL cholesterol (HDL-Chl). The M-group showed lower levels of phospholipids, total Chl, and HDL-Chl. In addition, the liver biochemical analysis indicated increases in TG, total Chl, and total bile acid (BA) in the H-group. Serum insulin levels did not change among the three groups (Table 1).
Response of the adipose tissue transcriptomes to the increased ratio of fat to carbohydrate
Differentially expressed genes in the liver and in the adipose tissues
L < H
L > H
Search for upstream regulators common among the liver and adipose tissues
We have analyzed the transcriptomic responses of the liver and adipose tissues to an increased ratio of F to C under isoenergetic conditions. In this study, three types of diets were adjusted with soybean oil to construct the C-F ratios, since it is the major oil in human diets. Soybean oil has some beneficial effects [45, 50], and hepatic transcriptomes can be influenced by oil and fat profiles . Although the fatty acid profile was different among three diets because of identical quantities of lard rich in saturated FA, it is crucial that the main energy resource was changed from C to F. The rats showed no between-group differences in body weight or in relative tissue weight (Additional file 2b); however, higher serum ALT levels were observed in the H-group compared with the L- and M-groups (Table 1). Because no significant fluctuations were observed among the other damage markers, the liver damage in the H-group seems to be limited in extent. This is in accordance with the fact that no significant enrichment of DEGs detected in GO terms related to liver damage, such as inflammation or fibrosis .
A comparison of L vs M transcriptomes in liver showed 126 (43 + 83) genes as differentially expressed (Fig. 2); this was less than the number of differentially expressed genes as compared to M vs H (131 + 106 genes) and L vs H (206 + 230 genes). This means that the transcriptome of the L-group was more closely related to that of the M-group than H-group (Fig. 1). Then, we analyzed LM43 + 83 DEGs to clarify C-F ratio dependency of hepatic transcriptome and we found 32 reversely regulated genes (i.e., upregulated in M-condition and downregulated in H-condition, or vice versa) (listed in Table 3). These reversely regulated liver DEGs can exert potential effects on lipid homeostasis; the upregulation of Acot1, Acsm2, and Agpat9 in the H-group may increase TG accumulation in the liver. Also, the role of LM43 + 83 DEGs in macronutrient conversion (e.g., amino acid to C and F to C) should be emphasized because our study was conducted under the isoenergetic conditions. In this context, the downregulation of Sds in the H-group may reduce utilization of amino acids for gluconeogenesis, and the upregulation of Gpd2 in the H-group may increase gluconeogenesis from glycerol produced by TG hydrolysis. Because the expression pattern of these genes was biphasic, the regulation of these metabolisms may have a balancing point close to the M-condition. As we used outbred Wistar rats, transcriptomic difference among the L-group and the M-group could be influenced by genetic or epigenetic differences between animals. Further indirect calorimetric studies with altered C-F ratios or animal strains are needed to clarify this metabolic regulation switching.
A question arising is whether these transcriptomic regulations are governed by any cellular signals common among these tissues. We computationally detected the downregulation of both insulin-PI3K-SREBF and PPAR alpha signals in the adipose tissues but not in the liver (Table 7). This suggests that both the anabolic signal of insulin (i.e., FA synthesis) and the catabolic signal of PPAR alpha (i.e., FA oxidation) are inhibited in adipose tissues. Because the rats in the H-group showed a growth rate (Additional file 2b) and serum insulin levels almost the same as in the L- and M-groups (Table 1), the suppression of insulin signals may be intrinsic to adipose tissues [33, 40, 47]. In the case of PPAR alpha signal, the low level of serum TG in the H-group might affect the concentration of FA in adipose tissues.
To investigate the effects of altered dietary C-F ratio, we compared with L vs M and L vs H DEGs. We found that hepatic genes for gluconeogenesis and lipid metabolism were reversely regulated, indicating that a turning point for gene expression switching from C to F as energy source may exist in the M-condition (C:F = 60:20) or a C-F ratio around M.
L vs H analyses revealed that high-fat diet upregulated Chl/BA synthesis in the liver and downregulated lipid synthesis in WAT and BAT. Also, our computational search for upstream regulators in these tissues suggested that insulin and PPAR alpha signals were downregulated both in WAT and BAT in the H-group.
In conclusion, the liver and adipose tissues differentially adapts to altered C-F by changing their gene expressions and not by merely responding to endocrine signals.
- LFD or L:
- MFD or M:
- HFD or H:
Methods and biochemical terms
Brown adipose tissues
Differentially expressed genes
False discovery rate
Insulin-induced gene protein
Ingenuity Pathway Analysis
Peroxisome proliferator-activated receptor
Peptidylprolyl isomerase F (cyclophilin D)
Polyunsaturated fatty acid
Sterol regulatory element-binding transcription factor
White adipose tissues
- Acot1 :
Acyl-CoA thioesterase 1
- Acsm2 :
Acyl-CoA synthetase medium-chain family member 2
- Acvr1c :
Activin A receptor, type IC
- Agpat9 :
1-Acylglycerol-3-phosphate O-acyltransferase 9
- Akr7a3 :
Aldo-keto reductase family 7, member A3 (aflatoxin aldehyde reductase)
- Apoa4 :
- Arntl/Clock :
Aryl hydrocarbon receptor nuclear translocator-like
- Atf3 :
Activating transcription factor 3
- Crem :
cAMP responsive element modulator
- Cyp :
- Dusp1 :
Dual specificity phosphatase 1
- Egfr :
Epidermal growth factor receptor
- Elovl5 :
ELOVL fatty acid elongase 5
- Fads1 :
Fatty acid desaturase 1
- Foxo1 :
Forkhead box O1A
- Gpd2 :
Glycerol-3-phosphate dehydrogenase 2, mitochondrial
- Gstt3 :
Glutathione S-transferase, theta 3
- Idi1 :
Isopentenyl-diphosphate delta isomerase 1
- Igf2 :
Insulin-like growth factor 2
- Il1a :
Interleukin 1 alpha
- Il6st :
Interleukin 6 signal transducer
- Lep :
- Lepr :
- Lyn :
LYN proto-oncogene, Src family tyrosine kinase
- Msmo1 :
Methylsterol monooxygenase 1
- Npas2 :
Neuronal PAS domain protein 2
- Pde3b :
Phosphodiesterase 3B, cGMP-inhibited
- Pdk1 :
Pyruvate dehydrogenase kinase, isozyme 1
- Per :
Period circadian clock
- Pik3r1 :
- Ppargc1b/Pgc1b :
Peroxisome proliferator-activated receptor gamma coactivator 1 beta
- Ppp1r1a :
Protein phosphatase 1, regulatory (inhibitor) subunit 1A
- Prf1 :
Perforin 1 (pore-forming protein)
- Prkaa :
Protein kinase, AMP-activated, alpha
- Scd1 :
Stearoyl-coenzyme A desaturase 1
- Sds :
- Shc1 :
SHC (Src homology 2 domain containing) transforming protein 1
- Srebf1 :
Sterol regulatory element-binding transcription factor 1
- Sqle :
- Sqrdl :
Sulfide quinone reductase-like
The authors thank the Cross-ministerial Strategic Innovation Promotion Program (SIP) (Grant No. 14532924) in Japan for their support.
This research was supported by the Cross-ministerial Strategic Innovation Promotion Program (SIP) (Grant No. 14532924) in Japan. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
All DNA microarray data (CEL files) presented in this publication have been deposited in the National Center of Biotechnology Information (NCBI) Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) and are accessible through the accession number GSE79867.
The experimental design was constructed and supervised by MT and TN. The animal experiments and biochemical analysis were performed by MS, KK, and YS. MT, YS, and TA worked on the DNA microarray assay. The manuscript was drafted and written by AY, TN, and MT. All authors read and approved the final manuscript.
The authors declare that they have no conflict of interests.
Consent for publication
All authors have agreed to its publication in Genes and Nutrition.
All animal experimental protocols were approved by the Animal Use Committee of the Takasaki University of Health and Welfare. All institutional and national guidelines for the care and use of laboratory animals were followed.
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