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1 Metabolism and Endocrinology Division, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan
2 Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
3 Department of Cellular Function, Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
4 Vascular System Division, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan
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Abstract |
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-ketoglutarate dependent oxidative reactions. Here, we demonstrate that JHDM2a also regulates metabolic genes related to energy homeostasis including anti-adipogenesis, regulation of fat storage, glucose transport and type 2 diabetes. Mice deficient in JHDM2a (JHDM2a–/–) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, which are hallmarks of metabolic syndrome. JHDM2a–/– mice furthermore exhibit fasted induced hypothermia indicating reduced energy expenditure and also have a higher respiratory quotient indicating less fat utilization for energy production. These observations may explain the obesity phenotype in these mice. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome. |
Introduction |
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Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing (Jenuwein 2006). A recent study showed that JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) catalyses removal of H3K9 mono- and dimethylation through iron and -ketoglutarate dependent oxidative reactions (Yamane et al. 2006) and plays essential roles during spermatogenesis in mice (Okada et al. 2007). We have recently reported that global demethylation of H3K9me1 and 2 occurs specifically during meiotic prophase in the male germ-cell-lineage and this is accompanied by an induction in JHDM2a expression Tachibana et al. 2007).
To evaluate whether JHDM2a is the enzyme responsible for this global H3K9 demethylation reaction, we established JHDM2a null mouse line that lacks the gene in all tissues in the body (designated JHDM2a–/–). The JHDM2a–/– male but not female mice showed a germ cell developmental defect after meiosis as reported (Okada et al. 2007) (MT, MN, YM and YS, unpublished data). Furthermore, we found that the male germ-lineage specific global H3K9 demethylation that normally occurs during meiosis was significantly suppressed in the JHDM2a–/– mice (Tachibana et al., manuscript in preparation). However, physiological roles of JHDM2a in adult still remain largely elusive. In this paper, we describe a novel role of JHDM2a in the metabolism of lipid, glucose, and the development of obesity. Our data indicate that JHDM2a is a key component of an epigenetic network controlling genes that are critical for energy homeostasis.
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Results |
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Glucose tolerance test (GTT) showed no significant differences between both genotypes; however, JHDM2a–/– mice had higher insulin levels than JHDM2a+/+ mice during the GTT despite their comparable glucose levels (Fig. 2c). Consistently, insulin tolerance test (ITT) demonstrated that insulin-mediated suppression of plasma glucose was severely impaired in JHDM2a–/– mice (Fig. 2d). These results suggested that whole-body insulin insensitivity is associated with adult onset obesity JHDM2a–/– mice and these mice mimic a pre-diabetic state. There were no marked differences in the weights of the kidneys or heart between JHDM2a+/+ and JHDM2a–/– mice (data not shown), but the weights of the epididymal, retroperitoneal and mesenteric WAT of JHDM2a–/– mice were significantly elevated relative to JHDM2a+/+ mice (Fig. 3a). Histological analysis demonstrated that WAT was hypertrophic and the average cell size was also markedly increased in JHDM2a–/– mice than in JHDM2a+/+ mice (Fig. 3b,c). There were no significant changes in BAT and skeletal muscle by histological and electron microscopic analysis (Fig. 3d and not shown). There were no differences in normalized liver weight or histology, nor were there any differences in levels of hepatic cholesterol, triglyceride or glycogen (Fig. 3e–i). Thus, the JHDM2a–/– mice developed a spectrum of biochemical abnormalities that are hallmarks of metabolic disease but liver metabolism is largely unaffected.
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(Tanaka et al. 2003; Wang et al. 2003), Pgc1 (Spiegelman & Flier 2001) in muscle and only expression of Dio2, previously associated with thermogenesis was significantly down-regulated in mRNA from BAT (Bianco et al. 2002; Watanabe et al. 2006). While expression of several genes implicated in adipocyte biology, obesity, and type 2 diabetes were differentially expressed in WAT, 30 additional genes related to energy homeostasis were also significantly down-regulated in WAT (Fig. 5a; see also Table S1 in Supporting Information). This group includes anti-adipogenic factors (Nr2f2 also known as CoupTFII and GATA2) (Tong et al. 2000; Xu et al. 2008; Okamura et al. 2009), an inhibitor of fat storage (Apoc1) (Jong et al. 2001), a key gene for glucose uptake (Slc2a4 better known as Glut4) (Rossetti et al. 1997; Stenbit et al. 1997), and a gene related to type 2 diabetes by meta-analysis of genome-wide association and large-scale replication study (ADAMTS9) (Zeggini et al. 2008).
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Because JHDM2a is a histone demethylase, we used a chromatin immunoprecipitation (ChIP) assay to determine whether the level of H3K9me2 at the promoter regions of these down-regulated genes might be directly altered by the loss of JHMD2a. Following the immunoprecipitation, a series of primer pairs from three genes from the set was used for this analysis (Fig. 5c). Interestingly, we detected an increase of H3K9me2 at the ADAMTS9 promoter in JHDM2a–/– WAT, while we observed very little changes in H3K4me2 with the same primer pair (Fig. 5c). Similar results were obtained for ApoC1 gene promoter (Fig. 5c). We also performed ChIP assays using an anti-JHDM2a antibody with chromatin from either WAT from control animals or 3T3-L1 pre-adipocytes and 3T3-L1 adipocytes. The results showed that JHDM2a was bound at the ADAMTS9 and ApoC1 gene promoters in WAT and 3T3-L1 adipocytes (Fig. 5d). Collectively, the above results support the notion that H3K9 demethylation activity is indeed selectively reduced in JHDM2a–/– mice and JHDM2a contributes to the expression of ADAMTS9 and ApoC1 genes by removing the silencing H3K9 methylation mark at their promoters.
Although we did not validate by qPCR, expression of genes related to thermogenesis (Dio2) (Bianco et al. 2002), adipogenesis (HSP105, Fos and SMAD1), susceptible to type 2 diabetes in human linkage analysis (LTF, Vasp, A2m and HSP70-2), an enzyme that catalyses conversion of cortisone to cortisol (HSD11b2) (Lee et al. 2008), a leptin signaling protein Mat2a (Ramani et al. 2008), the progesterone receptor gene (Pgr) (Honda et al. 1999), and the histidine decarboxylase gene (HDC) (Fulop et al. 2003) were also found to be reduced in JHDM2a–/– mice in the microarray experiments (Table S1 in Supporting Information). Interestingly, HDC null mice exhibit late onset obesity due to reduced energy expenditure (Fulop et al. 2003) and the vital role of Dio2 in energy expenditure and its anti-obesity role are well established in mice (Watanabe et al. 2006).
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Discussion |
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The major finding of this study is that deficiency of histone demethylase JHDM2a is associated with obesity and insulin resistance. JHDM2a regulates multiple genes that could be contributing to the metabolic phenotype via H3K9 demethylation reaction. The obesity phenotype is not due to differences in food intake or oxygen consumption but presumably through the alteration of RQ ratio suggesting a defect in fatty acid oxidation. The gene expression array studies showed a decrease in expression of anti-adipogenic factors Nr2f2 and Gata2 (Tong et al. 2000; Ohguchi et al. 2008; Xu et al. 2008) due to JHDM2a deficiency. Expression of genes that have been implicated as contributing to obesity or insulin resistance in animal models (Slc2A4, Apoc1, HDC and etc) (Rossetti et al. 1997; Stenbit et al. 1997; Jong et al. 2001; Fulop et al. 2003; Raychaudhuri et al. 2008) were also lower in the JHDM2a knockout mice. Most intriguingly, the gene expression array studies showed that Adamts9, recently identified as a gene associated with an increase in development of type II diabetes in clinical studies (Zeggini et al. 2008), was also altered in the JHDM2a–/– animals. A recent study demonstrated that differentiation and expansion of adipose tissue mass are linked to mechanisms associated with angiogenesis and vascularization (Rupnick et al. 2002). The Adamts disintegrin-protease system, together with plasminogen cascade, has been shown to be important for adipose tissue development (Voros et al. 2003; Lijnen 2008). Therefore, it is of interest that our study showed that Adamts9 may have an additional role in determining susceptibility to obesity and insulin resistance.
Currently the underlying mechanism that could directly explain the altered RQ remains to be elucidated. We may have missed the critical genes in our microarray studies because their expression might be transient at a time point not covered by our analysis. Consistent with this possibility, the alteration of RQ is observed only in the latter half of the dark cycle. Recently, the nuclear receptor corepressor 1 (NcoR1)–histone deacetylase 3 (HDAC3) complex, another histone modification enzyme complex, has been reported to regulate energy expenditure, adiposity and insulin sensitivity through circadian rhythm in mice where the NcoR1–HDAC3 interaction was disrupted by genetic means (Alenghat et al. 2008). Thus, it is conceivable that rhythmic changes in H3K9 methylation at certain genes may be involved which might be revealed in more detailed future studies.
While we were preparing the manuscript, Tateishi et al. (2009) reported that Jhdm2a-deficient mice developed obesity. They identified Ppar and Ucp1, two of the important genes involved in controlling energy balance, as direct targets of JHDM2a. They also showed that Jhdm2a expression is regulated by the β-adrenergic signaling pathway. Because the expression of these two genes as well as Jhdm2a is induced by β-adrenergic stimulation, they suggested that JHDM2a contributes to the cellular responses downstream of β-adrenergic signaling. Based on these findings, they proposed that the obesity phenotype is due to the loss of JHDM2a which is critical in regulating metabolic control through Ppar and β-adrenergic signaling pathways.
Although the overall obesity phenotype is similar between their study and our study, there are some subtle differences. First, they showed severe fat accumulation in skeletal muscle and liver of 7 month old JHDM2a knockout mice; however, abnormal fat accumulation was not observed in our 3 month old JHDM2a–/– mice. It is possible that this difference could indicate that fat deposition in skeletal muscle and liver occurs as the mice age. Second, unlike their analysis, expression of key genes involved in energy uncoupling and fatty acid oxidation, were not altered in either soleus (Ppar, Ppar, Pdk4 and Lcad) or BAT (Ucp1, Ucp2, Ucp3, Pdk4 or Lcad) of our JHDM2a–/– mice during light cycle (Fig. S2). However interestingly, Ppar was 50% lower in BAT during the dark cycle in our study (Fig. S2 in Supporting Information). Currently, the patho-physiological relevance of this reduction in Ppar remains to be elucidated since the PPAR targets involved in fatty acid oxidation or uncoupling were not decreased significantly in either BAT or soleus. However, we cannot rule out the possibility that differences in gene expression were too subtle to see in our 12 week old mice and the impaired expression of PPAR in BAT of JHDM2a–/– mice might cause the higher level of RQ during the dark cycle resulting in the abnormal fat accumulation in the JHDM2a–/– mice based on an essential role of PPAR in fatty acid oxidation (Reddy & Hashimoto 2001).
One of the potential mechanisms for the obese phenotype in our JHDM2a–/– mice would be that fatty acid uptake is increased due to low expression of ApoC1. ApoC1 has been shown to be a strong inhibitor of very low density lipoprotein (VLDL) binding to the VLDL receptor (Jong et al. 1996; Shachter et al. 1996) and VLDL receptor null mice (Frykman et al. 1995) are lean. Consistent with this prediction, ApoC1 transgenic mice are protected from obesity on the ob/ob background due to impaired peripheral uptake of fatty acids (Jong et al. 2001).
This report shows that changes in histone modification are a key component of an epigenetic network controlling energy homeostasis. Furthermore, work is required to unravel the causal relationship between diet-induced obesity and histone modifications in genes associated with nutritional balance. It is interesting to speculate that reduced JHDM2a activity may contribute to the pathogenesis of common forms of obesity and insulin resistance. Overall, our results indicate that modulation of H3K9 in chromatin may be a new target in the treatment of obesity and metabolic syndrome and indicate that the general relevance of epigenetic changes in histone modification to human nutrition and obesitystudies will be a fruitful area for further research.
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Experimental procedures |
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IgG-N1-1 is a rabbit polyclonal antibody that is directed against the NH2-terminus of mouse JHDM2a as described (Tachibana et al. 2007). The rabbit polyclonal antibody directed against the COOH-terminus of human JHDM2a (amino acids 1271–1321) was purchased from Novus (Littleton, CO; Catalog Number: NB100-77282).
Generation of JHDM2a–/– mice
To generate the JHDM2a–/– mice, we constructed a knock-in-type vector that replace the mouse JHDM2a genome containing exons 20–25 with the corresponding cDNA (Fig. 1a). TT2 embryonic stem cells were used to transfer a targeting vector using standard technique. Mice carrying a JHDM2a knock-in allele (JHDM2a+/KI) was identified by Southern blotting (Fig. 1b). JHDM2a+/KI mice were then crossed with tissue-non-specific alkaline phosphatase-Cre knock-in mice, which express the Cre recombinase in primordial germ cells. Subsequently, we obtained JHDM2a+/
mice from the progenies, which carried JHDM2a allele lacking exons 20–25 (Fig. 1a). Loss of JHDM2a protein was confirmed by immunoblot analyses using JHDM2a/ ES cells (Fig. 1c). The chimeric male mice were originally bred to a C57BL/6 and then backcrossed for four to five generations to C57BL/6.
Animal experiments
Mice experiments were performed on age matched, individually housed female mice except body weight measurements in Fig. 2a. All animals were housed in a temperature-controlled (24 °C) facility with 12 h light/dark cycles (08:00 to 20:00 light) and allowed free access to water and chow diet containing 8.5% fat (CMF; Oriental Yeast, Tokyo, Japan). For the fasting experiments, mice were fasted for 12 h from the beginning of dark cycle. Food intake was monitored daily for 1 week and core body temperature was monitored using a rectal thermometer at the end of dark cycle. Energy expenditure was measured for 4 days by indirect calorimetry as described previously (MK-5000RQ; Muromachi, Tokyo, Japan) (Sakakibara et al. 2009). All mice were killed at the end of dark cycle and blood was taken from inferior vena cava and plasma was separated. The epididymal, mesenteric and retroperitoneal WAT and liver were removed, weighed, frozen in liquid nitrogen and stored at –80 °C. All mice protocols were approved by the Animal Care and Use Committee of the University of Tokyo.
Metabolite measurements
Total lipids were extracted from 50 mg of liver as previously described (Inagaki et al. 2005). Triglyceride and cholesterol contents of liver and plasma concentrations were measured using Triglyceride E-test (Wako Pure Chemical, Osaka, Japan) and Cholesterol E-test (Wako Pure Chemical) respectively. For glycogen assay, glycogen was extracted from 100 mg liver in 400 µL of 4% percholic acid under the frozen condition. Isolated glycogen was dissolved in 1 mL of 0.2 M acetate buffer (pH 4.8) containing 50 mM KHCO3 and hydrolyzed by incubating for 2 h at 40 °C with 20 units of amyloglucosidase (Sigma, St Louis, MO). Resulting glucose and plasma glucose level was determined using Glucose C2-test (Wako Pure Chemical). Plasma NEFA and total ketone body levels were determined by NEFA C-test (Wako Pure Chemical) and Autokit Total Ketone Bodies (Wako Pure Chemical). Plasma insulin, leptin and adiponectin levels were determined by ELISA using an insulin immunoassay kit (Shibayagi, Gunma, Japan), a mouse leptin immunoassay kit (R&D systems, Minneapolis, MN) and a mouse adiponectin immunoassay kit (R&D systems) according to the manufacturer’s instructions.
Glucose and insulin tolerance tests
Mice were fasted for 12 h and then given an intraperitoneal injection of glucose (2 g per kg body weight) (Fujino et al. 2003) for GTT. For ITT, non-fasted mice were injected intraperitoneally 4 h after beginning of light cycle with 1 U per kg body weight of human insulin (Eli Lilly & Co., Indianapolis, IN). Blood samples for glucose and insulin measurements were obtained from the tail vein at the indicated times.
Histology and morphometric analysis of tissues
Adipose and liver tissues were analyzed by hematoxylin and eosin staining. Morphometric analysis of epididymal WAT from 50 or more cells from six different animals per genotype was performed with IMAGEJ software (NIH, Bethesda, MD).
Affymetrix microarray
Total RNA for microarray analyses was extracted from two independent JHDM2a–/– and JHDM2a+/+ livers, WAT, BAT and skeletal muscles using ISOGEN (Wako Pure Chemical Industries) or Qiagen Lipid Tissue Mini Kit (Qiagen Sciences, Germantown, MD). The expression of 
39 000 transcripts was measured by using Affymetrix Mouse Genome 430 2.0 arrays as described (Ohguchi et al. 2008).
Chromatin immunoprecipitation
For ChIP using anti-H3K9me2, anti-H3K9me3 and anti-H3K4me2 antibodies, ChIP assay was performed as previously described (Kimura et al. 2008). Briefly, mouse adipose tissues (
0.2 g) were chopped into small pieces with a mortar and pestle, and cross-linked for 15 min at room temperature (RT) with formaldehyde at a final concentration of 1% (w/v) in phosphate-buffered saline (PBS) (Ohguchi et al. 2008). The samples were subsequently washed twice with PBS containing protease inhibitors (0.5 mM phenylmethylsulfonylfluoride, 2.8 µg/mL aprotinin, 10 µg/mL leupeptin and 5 µg/mL pepstatin A), and then tissue samples were disaggregated using Dounce homogenizer. After centrifugation, the pellets were resuspended in SDS lysis buffer (50 mM Tris–HCl at pH 8.1, 1% SDS, and 10 mM EDTA) containing protease inhibitors, and sonicated to generate 200–1000 bp DNA fragment. For ChIP using anti-JHDM2a antibody, WAT or 3T3-L1 cells were first cross-linked with 1 mM of Dithiobis(succinimidiylproponate) (Pierce, Rockford, IL) for 30 min at RT, washed once with ice-cold PBS, and then a second cross-linking was performed with 1% formaldehyde for 10 min at RT as described previously (Ohguchi et al.). ChIP was performed with mouse monoclonal anti-H3K9me2 (ab1220; Abcam, Cambridge, MA), mouse monoclonal anti-H3K9me3 (2F3; gift from Dr H. Kimura, Osaka University), mouse monoclonal anti-H3K4me2 (CMA303; gift from Dr H. Kimura, Osaka University), anti-JHDM2A (NB100-77282; Novus) or control IgG using the primers in Table S2 in Supporting Information.
Quantitative real-time PCR
RNA was prepared and qPCR performed as previously described (Inagaki et al. 2005). Primer sequences are listed in Table S2 in Supporting Information.
Cell culture
3T3-L1 mouse fibroblasts were differentiated into adipocytes using a standard differentiation protocol as previously described (Okamura et al. 2009; Wakabayashi et al. 2009). Briefly, cells were maintained Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum (basal medium) at 37 °C. 3T3-L1 cell differentiation into adipocytes was induced by treatment of confluent cells first for 2 days with insulin (1 µg/mL), 0.25 µM dexamethasone, and 0.5 mM isobutylmethylxanthine (MDI cocktail) in basal medium. 3T3-L1 cells were cultured for 2 days with insulin (1 µg/mL) alone in the same medium. The cells were then returned to the basal medium, which was replenished every other day as described (Okamura et al. 2009; Wakabayashi et al. 2009).
RNA interference
To deplete cellular JHDM2a, siGENOME small interfering RNAs (siRNAs) targeting JHDM2a mRNA (target sequence of 5'-CCGAUGACCUUUCAGAUAA-3') was purchased from Dharmacon, Inc. (Chicago, IL, USA). As a negative control, siGENOME non-targeting control siRNA pool #2 (D-001206-14-05) was used. For transfection, cells were transfected with the siRNAs for JHDM2a (1.5 µL each, final concentration of 10 nM) plus 5 µL Lipofectamine RNAiMax reagent (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions with modifications as follows. Lipofectamine RNAiMax–siRNA complexes were formed in 0.5 mL of serum free Opti-MEM reduced serum medium (Gibco, Grand Island, NY) for 10 min at RT and then added to each well. Cells were then seeded at density of 1.2 x 105 cells/well in 2.5 mL of growth medium onto the lipofectamine RNAiMax–siRNA complexes. Cells were cultured four more days until they reached to confluence. Medium was changed every other day. At 2 days post-confluence, the second transfection was performed and cells were induced to differentiate by exposure to differentiation medium containing of MDI for siRNA for JHDM2a.
Statistical analysis
Statistical differences were determined by Student’s t-test. Statistical significance is displayed as *P < 0.05 or **P < 0.01.
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Acknowledgements |
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Footnotes |
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These authors contributed equally to this work.
* jmsakai-tky{at}umin.ac.jp or yshinkai{at}virus.kyoto-u.ac.jp |
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Received: 10 March 2009
Accepted: 14 May 2009
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