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Intestinal MYC modulates obesity-related metabolic dysfunction

Nature Metabolism volume 3, pages 923–939 (2021)Cite this article

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Abstract

MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

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Fig. 1: MYC was induced in the intestines of humans and mice with obesity.
Fig. 2: MycΔIE/+ mice displayed less obesity and hepatic steatosis under HFD challenge.
Fig. 3: Intestine-specific inducible Myc disruption ameliorated HFD-induced obesity and hepatic steatosis.
Fig. 4: Intestinal Myc disruption or inhibition increased GLP-1 production and secretion.
Fig. 5: Intestinal Myc disruption reduced ceramide production and secretion.
Fig. 6: Cers4 was a MYC target gene in the intestine.
Fig. 7: Inhibition of MYC in the intestine improved HFD-induced hepatic steatosis.
Fig. 8: Inhibition of MYC in the intestine improved HFCFD-induced liver fibrosis.

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Data availability

Transcriptomic data have been deposited in the Gene Expression Omnibus under accession code GSE155460. Source data are provided with this paper.

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Acknowledgements

We thank Q. Wang, D. Lu and J. Zhao for help with animal dissection and sample collection, and L. Byrd for assistance with the mouse protocols. We thank J. M. Sedevy for providing the Mycfl/fl mice, D. L. Gumucio for transferring the villin-cre mice and P. Chambon for providing the villin-ERT2-cre mice. This study was supported by the National Cancer Institute Intramural Research Program (ZIA BC005562; to F.J.G.) and the Outstanding academic leaders plan of Shanghai (grant no. 2018BR07; to W.L.). S.Y. was supported by a visiting fellowship from the First Affiliated Hospital, University of Science and Technology of China.

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Authors and Affiliations

  1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Yuhong Luo, Shoumei Yang, Shogo Takahashi, Lulu Sun, Jie Cai, Kristopher W. Krausz, Henrique B. Dias, Cen Xie & Frank J. Gonzalez

  2. Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, P.R. China

    Xuan Wu & Weiwei Liu

  3. Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University, Shanghai, P.R. China

    Xuan Wu & Weiwei Liu

  4. Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA

    Shogo Takahashi

  5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China

    Xiaozhen Guo & Cen Xie

  6. Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Oksana Gavrilova

  7. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P.R. China

    Changtao Jiang

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  1. Yuhong Luo
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Contributions

Y.L., S.Y., X.W., L.S. and J.C. performed experiments. K.W.K. helped with the lipidomics analysis. C.X. and X.G. helped with RNA-seq analysis. H.B.D. helped with immunohistochemistry staining. C.J., C.X. and S.T. provided valuable suggestions about experimental design. W.L. collected human ileum biopsies. O.G. helped with indirect calorimetry. Y.L. and F.J.G. were responsible for the study concept and design. Y.L. and F.J.G. wrote the manuscript. W.L. and F.J.G. supervised the study. All authors approved the final version of the manuscript.

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Correspondence to Weiwei Liu or Frank J. Gonzalez.

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Peer review information Nature Metabolism thanks William Holland, Ömer Yilmaz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt.

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Extended data

Extended Data Fig. 1 Homozygous loss of MYC in the intestine was lethal.

Mycfl/fl and MycΔIE mice at 21 days of age. a, Photos of Mycfl/fl and MycΔIE mice. b, Representative H&E staining of intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. c, Representative Alcian Blue staining of intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 100 µm. d, Number of goblet cells. n = 30. e, Body weight. f, Liver weight. g, Small intestine length. h, Colon length. i, Small intestine length to body weight ratio. j, Colon length to body weight ratio. k, Serum ALT. l, Serum AST. m, Serum triglyceride. n, Serum total cholesterol. o, Hepatic triglyceride. p, Hepatic total cholesterol. e-p, n = 9 for Mycfl/fl mice and n = 4 for MycΔIE mice. q, The mRNA levels of indicated genes in the intestine of Mycfl/fl and MycΔIE mice. n = 5 for Mycfl/fl mice and n = 4 for MycΔIE mice. * or ** P = 0.0030, 0,0167, 0.0040, 0.0402, 0.0235, 0.0344, from left to right. N.D., not detectable. r, Western blot analysis of indicated proteins in the intestine of Mycfl/fl and MycΔIE mice. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using a two-tailed Student’s t-test (d-q).

Source data

Extended Data Fig. 2 Generation of mice with heterozygous loss of MYC in the intestine.

a, Myc mRNA levels in different tissues of Mycfl/+ and MycΔIE/+ mice. n = 6. b, The mRNA levels of indicated genes in the intestine of Mycfl/+ and MycΔIE/+ mice. n = 7. c, The protein levels of MYC in the intestine of Mycfl/+ and MycΔIE/+ mice. d, Representative H&E staining of intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 100 µm. e, Representative Alcian Blue staining of intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 100 µm. f, Number of goblet cells. n = 30. g, Representative immunohistochemistry staining of lysozyme on intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. h, Number of Paneth cells. n = 30. i, Representative immunohistochemistry staining of synaptophysin on intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. j, Number of enteroendocrine cells. n = 9. k, Representative BrdU staining of intestine sections (n = 5 mice/group, 9 images/mouse). Scale bar, 100 µm. l, BrdU labeling index. n = 5. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using a two-tailed Student’s t-test (a,b,f,h,j,l).

Source data

Extended Data Fig. 3 Intestinal cell proliferation, hepatic gene expression and energy expenditure of MycΔIE/+ mice under HFD.

a-c, Mycfl/+ and MycΔIE/+ mice were fed a HFD for 18 weeks. Representative of n = 2 experiments. a, Body weight curve. ** or ***P = 0.0003, 0.0002, < 0.0001, 0.0008, 0.0009, 0.0008, 0.0008, 0.0008, 0.0007, 0.0010, 0.0004, 0.0003, 0.0005, 0.0003, < 0.0001, 0.0004, 0.0004 from 2w to 18w. b, Liver weight. a,b, n = 7 for Mycfl/+ mice and n = 6 for MycΔIE/+ mice. c, Representative H&E and Oil Red O staining of liver sections (n = 4 mice/group, 3 images/mouse). Scale bar, 50 µm. d-f, Mycfl/+ and MycΔIE/+ mice were fed a HFD for 10 weeks. Representative of n = 3 experiments. d, Representative BrdU staining of intestine sections (n = 5 mice/group, 9 images/mouse). Scale bar, 100 µm. right, BrdU labeling index, n = 5. e, Hepatic expression of genes involved in lipid synthesis, transport and β-oxidation. n = 7. * or ** or *** P = 0.0412, 0.0456, 0.0165, 0.0216, 0.0002, 0.0071, 0.0027, 0.0124, 0.0022, from left to right. f, Hepatic expression of genes involved in glycolysis (left) and gluconeogenesis (right). n = 7. * or ** or *** P = 0.0376, 0.0231, 0.0235, 0.0007, 0.0047, 0.0004, 0.0067, 0.0015, 0.0047, 0.0045, 0.0407, 0.0175, 0.0058, from left to right. g-i, Mycfl/+ and MycΔIE/+ mice were fed a HFD for 2 weeks. n = 6. Representative of n = 3 experiments. g, Fecal triglyceride. h, Fecal total cholesterol. i, Fecal NEFA. j-n, Mycfl/+ and MycΔIE/+ mice were fed a HFD for 4 weeks. j, Total energy expenditure. k, Oxygen consumption rate. l, Respiratory exchange ratio. m, Total activity. n, Food intake. j-m, n = 6. n, n = 5 for Mycfl/+ and n = 4 for MycΔIE/+. o, Representative immunohistochemistry staining of UCP-1 on subcutaneous white adipose tissues from Mycfl/+ and MycΔIE/+ mice fed a HFD for 10 weeks (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using a two-tailed Student’s t-test (a,b,d-n).

Source data

Extended Data Fig. 4 Generation of mice with inducible loss of MYC in the intestine.

a, Myc mRNA levels in different tissues of Mycfl/fl and MycΔIE, ERT2 mice treated with tamoxifen. n = 4. b, The mRNA levels of indicated genes in the intestine of Mycfl/fl and MycΔIE, ERT2 mice treated with tamoxifen. n = 5. c, Representative H&E staining of intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 100 µm. d, Representative Alcian Blue staining of intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 100 µm. e, Number of goblet cells. n = 30. f, Representative immunohistochemistry staining of lysozyme on intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. g, Number of Paneth cells. n = 30. h, Representative immunohistochemistry staining of synaptophysin on intestine sections (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. i, Number of enteroendocrine cells. n = 9. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using a two-tailed Student’s t-test (a,b,e,g,i).

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Extended Data Fig. 5 Metabolic parameters of MycΔIE, ERT2 mice under chow diet.

a, Representative immunohistochemistry staining of MYC on intestine sections from Mycfl/+ and MycΔIE/+ mice (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. b, Representative immunohistochemistry staining of MYC on intestine sections from Mycfl/fl and MycΔIE, ERT2 mice (n = 3 mice/group, 3 images/mouse). Scale bar, 50 µm. c, Representative in situ hybridization of Myc on intestine sections from Mycfl/+ and MycΔIE/+ mice (n = 2 mice/group, 3 images/mouse). Scale bar, 50 µm. d, Representative in situ hybridization of Myc on intestine sections from Mycfl/fl and MycΔIE, ERT2 mice (n = 2 mice/group, 3 images/mouse). Scale bar, 50 µm. e-n, Mycfl/fl and MycΔIE, ERT2 mice were weekly injected with tamoxifen for 6 weeks from 8 weeks of age. e, Glucose tolerance test. f, Insulin tolerance test. g, Body weight. h, Liver weight. i, Serum ALT. j, Serum AST. k, Serum triglyceride. l, Serum total cholesterol. m, Hepatic triglyceride. n, Hepatic total cholesterol. e-n, n = 4. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using a two-tailed Student’s t-test (e-n).

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Extended Data Fig. 6 RNA-seq analysis of MycΔIE, ERT2 mice fed a HFD for 2 weeks.

a-j, Mycfl/fl and MycΔIE, ERT2 mice were injected with tamoxifen and fed a HFD for 2 weeks. a, Body weight curve. b, Liver weight. c, Serum ALT. d, Serum AST. e, Serum triglyceride. f, Serum total cholesterol. g, Hepatic triglyceride. h, Hepatic total cholesterol. a-h, n = 7. i, Glucose tolerance test. j, Insulin tolerance test. i,j, n = 9 for Mycfl/fl mice and n = 10 for MycΔIE, ERT2 mice. *P = 0.0113 (GTT, 30 min), 0.0497 (GTT, 60 min), 0.0103 (ITT, 60 min), 0.0224 (ITT, 90 min). All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using a two-tailed Student’s t-test (a-j). The PCA plot (k), volcano plot (l) and pathway enrichment (m) of the RNA-seq data from the intestines of Mycfl/fl and MycΔIE, ERT2 mice injected with tamoxifen and fed a HFD for 2 weeks.

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Extended Data Fig. 7 Intestinal Myc disruption improved obesity and fatty liver through ceramide reduction.

Mycfl/+ and MycΔIE/+ mice were fed a HFD and daily i.p. injected with vehicle or ceramide for 6 weeks. Representative of n = 2 experiments. a, Glucose tolerance test. b, Insulin tolerance test. a,b, * or **P = 0.0027, 0.0031, 0.0340, 0.0074, 0.0139, 0.0428, 0.0179, from left to right, MycΔIE/+ Vehicle group versus Mycfl/+ Vehicle group. # or ##P = 0.0138, 0.0341, 0.0120, from left to right, MycΔIE/+ Ceramide group versus MycΔIE/+ Vehicle group. c, GTT AUC. d, ITT AUC. e, Liver weight. f, Serum ALT. g, Serum AST. h, Serum triglyceride. i, Serum total cholesterol. j, Hepatic triglyceride. k, Hepatic total cholesterol. l, The mRNA levels of indicated genes in the liver. * or ** or ***P = 0.0325, 0.0062, 0.0383, 0.0145, 0.0027, 0.0007, 0.0013, 0.0005, 0.0319, from left to right, MycΔIE/+ Vehicle group versus Mycfl/+ Vehicle group. # or ## or ###P = 0.0091, < 0.0001, 0.0059, 0.0007, 0.0023, 0.0089, 0.0345, 0.0477, from left to right, MycΔIE/+ Ceramide group versus MycΔIE/+ Vehicle group. a-l, n = 7 for Mycfl/+ Vehicle group. n = 6 for MycΔIE/+ Vehicle group and MycΔIE/+ Ceramide group. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using one-way ANOVA followed by Tukey’s multiple comparisons test (c-l), or two-way ANOVA followed by Dunnett’s multiple comparisons test (a,b). m, Representative H&E and Oil Red O staining of liver sections (n = 4 mice/group, 3 images/mouse). Scale bar, 100 µm.

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Extended Data Fig. 8 Intestinal Myc disruption decreased SMPD3 levels.

a, Protein levels of SMPD3 in the intestine of Mycfl/+ and MycΔIE/+ mice fed a HFD for 2 weeks. b, Protein levels of SMPD3 in the intestine of C57BL/6 N mice first fed a HFD for 6 weeks and then daily gavaged with vehicle or 50 mg/kg 10058-F4 while maintained on a HFD for another 8 weeks. c, Schematic diagram of the mouse Smpd3 promotor illustrating the predicted Ebox sites in the regulatory region and the fragments used for the luciferase reporter assay. d, Luciferase reporter assay of the mouse Smpd3 promoter activity. n = 3. e, ChIP assay with MC38 cells transfected with empty backbone or MYC overexpression plasmid and treated with vehicle or 40 µM 10058-F4 for 48 h. n = 3 for α-MYC and IgG groups, n = 1 for α-H3 group. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using two-way ANOVA followed by Tukey’s multiple comparisons test (d,e).

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Extended Data Fig. 9 CERS4 regulated ceramide production in intestinal organoids.

a, Cers4 mRNA levels in the intestine of C57BL/6 N mice fed a chow diet or HFD for 2 weeks or 15 weeks. n = 5 for 2w chow, 15w chow and 15w HFD. n = 6 for 2w HFD. b-e, Intestinal organoids were isolated from Mycfl/+ mice fed a HFD for 2 weeks and infected with lentiviruses carrying scramble siRNA (scramble) or Cers4 shRNA (shCers4). b, Cers4 mRNA levels in intestinal organoids. n = 4. c, CERS4 protein levels in intestinal organoids. d, Ceramide levels in the intestinal organoids. n = 6. e, Ceramide levels in the culture medium of intestinal organoids. n = 6. f-i, Intestinal organoids were isolated from Mycfl/+ and MycΔIE/+ mice fed a HFD for 2 weeks and infected with control lentiviruses (Lv-Empty) or lentiviruses carrying Cers4 cDNA (Lv-Cers4). f, Cers4 mRNA levels in intestinal organoids. n = 4. g, CERS4 protein levels in intestinal organoids. h, Ceramide levels in the intestinal organoids. n = 6. i, Ceramide levels in the culture medium of intestinal organoids. n = 6. h-i, * or **P = 0.0046, 0.0016, 0.0309, 0.0229, 0.0212, 0.0136, 0.0018, 0.0012, 0.0031, from left to right, MycΔIE/+ Lv-Empty group versus Mycfl/+ Lv-Empty group. # or ##P = 0.0012, 0.0492, 0.0015, 0.0072, 0.0416, from left to right, MycΔIE/+ Lv-Cers4 group versus MycΔIE/+ Lv-Empty group. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using a two-tailed Student’s t-test (a,b,d,e), or one-way ANOVA followed by Tukey’s multiple comparisons test (f,h,i).

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Extended Data Fig. 10 The effect of 10058-F4 on metabolic syndrome was dependent on intestinal MYC.

Mycfl/+ and MycΔIE/+ mice were fed a HFD and treated with vehicle or 10058-F4 for 8 weeks. a, Body weight curve. ** or ***P = 0.0013 for 2w, < 0.0001 for 3–8w, MycΔIE/+ Vehicle group versus Mycfl/+ Vehicle group. # or ## or ###P = 0.0307, 0.0033, 0.0011, 0.0001, 0.0015, 0.0001, < 0.0001 for 2–8w, Mycfl/+ 10058-F4 group versus Mycfl/+ Vehicle group. b, Fat mass. c, Lean mass. d, Liver weight. e, Glucose tolerance test. f, Insulin tolerance test. e,f, * or ** or ***P = 0.0403, 0.0050, 0.0144, 0.0175, 0.0298, 0.0014, 0.0004, from left to right, MycΔIE/+ Vehicle group versus Mycfl/+ Vehicle group. # or ##P = 0.0330, 0.0226, 0.0099, 0.0041, from left to right, Mycfl/+ 10058-F4 group versus Mycfl/+ Vehicle group. g, GTT AUC. h, ITT AUC. i, Insulin curve in response to glucose. **P = 0.0031 (0 min), 0.0078 (75 min), MycΔIE/+ Vehicle group versus Mycfl/+ Vehicle group. # or ##P = 0.0025 (0 min), 0.0140 (75 min), Mycfl/+ 10058-F4 group versus Mycfl/+ Vehicle group. j, insulin levels at 0 min and 15 min post glucose load. k, Serum ALT. l, Serum AST. m, Serum triglyceride. n, Serum total cholesterol. o, Hepatic triglyceride. p, Hepatic total cholesterol. a-p, n = 8. All data are presented as mean ± S.E.M. of biologically independent samples, analyzed using one-way ANOVA followed by Tukey’s multiple comparisons test (b-d,g,h,k-p), two-way ANOVA followed by Tukey’s multiple comparisons test (a,e,f,i), or a two-tailed paired t-test (j). q, Representative H&E staining of liver (top) and intestine sections (bottom), and Oil Red O staining of liver sections (middle) (n = 4 mice/group, 3 images/mouse). Scale bar, 100 µm.

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Luo, Y., Yang, S., Wu, X. et al. Intestinal MYC modulates obesity-related metabolic dysfunction. Nat Metab 3, 923–939 (2021). https://doi.org/10.1038/s42255-021-00421-8

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