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Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch

Abstract

Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), specialized for energy expenditure through thermogenesis, potently counteracts obesity. Factors that induce brown adipocyte commitment and energy expenditure would be a promising defence against adiposity. Here, we show that Lgr4 homozygous mutant (Lgr4m/m) mice show reduced adiposity and resist dietary and leptin mutant-induced obesity with improved glucose metabolism. Lgr4m/m mice show a striking increase in energy expenditure, and exhibit brown-like adipocytes in WAT depots with higher expression of BAT and beige cell markers. Furthermore, Lgr4 ablation potentiates brown adipocyte differentiation from the stromal vascular fraction of epididymal WAT, partially through retinoblastoma 1 gene (Rb1) reduction. A functional low-frequency human LGR4 variant (A750T) has been associated with body mass index in a Chinese obese-versus-control study. Our results identify an important role for LGR4 in energy balance and body weight control through regulating the white-to-brown fat transition.

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Figure 1: Lgr4m/m mice are resistant to obesity and its metabolic consequences.
Figure 2: Ablation of Lgr4 increases energy expenditure.
Figure 3: Ablation of Lgr4 induces white-to-brown fat transition.
Figure 4: Ablation of Lgr4 potentiates the differentiation of SVF from eWAT towards brown-like adipocytes.
Figure 5: Lgr4 ablation-induced brown adipocyte differentiation of eWAT SVF is partially through repressing Rb1 expression.
Figure 6: The association of LGR4 with human obesity.

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References

  1. Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Cypess, A. M. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat. Med. 19, 635–639 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Enerback, S. The origins of brown adipose tissue. N. Engl. J. Med. 360, 2021–2023 (2009).

    Article  PubMed  Google Scholar 

  6. Petrovic, N. et al. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J. Biol. Chem. 285, 7153–7164 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Song, Y. et al. CRTC3 links catecholamine signalling to energy balance. Nature 468, 933–939 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vegiopoulos, A. et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328, 1158–1161 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rosenwald, M., Perdikari, A., Rulicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, Y. H., Petkova, A. P., Mottillo, E. P. & Granneman, J. G. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schulz, T. J. et al. Identification of inducible brown adipocyte progenitorsresiding in skeletal muscle and white fat. Proc. Natl Acad. Sci. USA 108, 143–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Atit, R. et al. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164–176 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Scime, A. et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1alpha. Cell Metab. 2, 283–295 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Bostrom, P. et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Barker, N. & Clevers, H. Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology 138, 1681–1696 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. de Lau, W. et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476, 293–297 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Snippert, H. J. et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 327, 1385–1389 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Li, X. Y. et al. G protein-coupled receptor 48 upregulates estrogen receptor alpha expression via cAMP/PKA signaling in the male reproductive tract. Development 137, 151–157 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, J. et al. GPR48 increases mineralocorticoid receptor gene expression. J. Am. Soc. Nephrol. 23, 281–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Weng, J. et al. Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc. Natl Acad. Sci. USA 105, 6081–6086 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Carmon, K. S., Gong, X., Lin, Q., Thomas, A. & Liu, Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc. Natl Acad. Sci. USA 108, 11452–11457 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kettunen, J. et al. Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci. Int. J. Obes. (Lond) 33, 1235–1242 (2009).

    Article  CAS  Google Scholar 

  27. Thorleifsson, G. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Calo, E. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mercader, J. et al. Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice. Am. J. Physiol. Endocrinol. Metab. 297, E184–E193 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Magenta, A. et al. MyoD stimulates RB promoter activity via the CREB/p300 nuclear transduction pathway. Mol. Cell Biol. 23, 2893–2906 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hsu, S. Y., Liang, S. G. & Hsueh, A. J. Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol. Endocrinol. 12, 1830–1845 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Yano, K. et al. A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty. J. Clin. Endocrinol. Metab. 80, 1162–1168 (1995).

    CAS  PubMed  Google Scholar 

  33. Gozu, H. I. et al. Similar prevalence of somatic TSH receptor and Gsalpha mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey. Eur. J. Endocrinol. 155, 535–545 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Achrekar, S. K., Modi, D. N., Meherji, P. K., Patel, Z. M. & Mahale, S. D. Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea. J. Assist. Reprod. Genet. 27, 317–326 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhang, M. et al. Intrinsic differences in the response of the human lutropin receptor versus the human follitropin receptor to activating mutations. J. Biol. Chem. 282, 25527–25539 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. James, W. P. et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N. Engl. J. Med. 363, 905–917 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Mazerbourg, S. et al. Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol. Endocrinol. 18, 2241–2254 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Dali-Youcef, N. et al. Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure. Proc. Natl Acad. Sci. USA 104, 10703–10708 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hansen, J. B. et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl Acad. Sci. USA 101, 4112–4117 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kang, S. et al. Effects of Wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1alpha. Mol. Cell Biol. 25, 1272–1282 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Park, C. J. et al. Genetic rescue of nonclassical ERalpha signaling normalizesenergy balance in obese Eralpha-null mutant mice. J. Clin. Invest. 121, 604–612 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yoshizawa, T. et al. The transcription factor ATF4 regulates glucose metabolismin mice through its expression in osteoblasts. J. Clin. Invest. 119, 2807–2817 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Styrkarsdottir, U. et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497, 517–520 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Folch, J. & Lees, M. Sloane Stanley, G.H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497–509 (1957).

    CAS  PubMed  Google Scholar 

  45. Zhang, Y. et al. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc. Natl Acad. Sci. USA 106, 19860–19865 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, Z. et al. Ginsenoside Re reduces insulin resistance through inhibition of c-Jun NH2-terminal kinase and nuclear factor-kappaB. Mol. Endocrinol. 22, 186–195 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tschop, M. H. et al. A guide to analysis of mouse energy metabolism. Nat. Methods 9, 57–63 (2012).

    Article  Google Scholar 

  49. De Bakker, P. I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (nos 81030011, 30725037, 81100601, 81100634 and 30890043), the Sector Funds of Ministry of Health (no. 201002002) and the National Key New Drug Creation and Manufacturing Program of the Ministry of Science and Technology (2012ZX09303006-001). We thank S. Lai (Johns Hopkins School of Medicine) and D. Cai (Albert Einstein College of Medicine) for revision of the manuscript. We thank N. Fan and F. Li for their technical assistance in immunostaining and animal experiments.

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Authors and Affiliations

Authors

Contributions

J.W. and G.N. conceived the project and designed the experiments, and J.W. carried out most of the experiments. J.W., R.L. and G.N. wrote the paper. F.W. carried out a subset of in vitro experiments. J.H., J.S., B.C., W.G., Y.Z. and W.W. recruited the obese patients and normal individuals and contributed with the human study. X.L. assisted with statistical analysis. R.L. carried out SVF related experiments. M.C., Y.K. and X.Z. contributed with genotyping and animal experiments. Q.M. and R.W. carried out DNA isolation and sequencing. Z.Z. contributed with fat content scanning. X.X. contributed comments and advice on the manuscript. M.L. contributed with Lgr4m/m mice and valuable materials. All authors were involved in editing the manuscript.

Corresponding author

Correspondence to Guang Ning.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Improved metabolic parameters in Lgr4m/m mice fed CD or HFD and Lgr4/leptin double mutant mice.

(a) Fat mass and lean mass content normalized to body weight in wild-type and Lgr4m/m mice. (b) Blood glucose levels of CD-fed 8-week and 40-week wild-type and Lgr4m/m mice fasted for 16h (n = 8–12 for each group). (c) Blood glucose levels of CD-fed 8-week wild-type and Lgr4m/m mice fasted for 12 h, 36 h and 48 h (n = 10-17 for each group). (d) Plasma insulin levels of CD-fed wild-type and Lgr4m/m mice at 0, 30 and 60 min after glucose injection (n = 8-9 for each group). (e, f) Plasma TG levels (e) and total cholesterol levels (f) of wild-type and Lgr4m/m mice fed CD (n = 9 for each group). (g) Blood glucose levels of HFD-fed 12-week wild-type and Lgr4m/m mice fasted for 16h (n = 10-13 for each group). (h) Plasma insulin levels of HFD-fed wild-type and Lgr4m/m mice at 0, 30 and 60 min after glucose injection (n = 8-11 for each group). (i) Fat mass and lean mass content normalized to body weight in ob/ob and m/m;Ob mice. (j, k) Glucose tolerance test (j) and insulin tolerance test (k) in ob/ob and m/m;Ob mice fed CD (n = 6 for each group). (l, m) Plasma TG levels (l) and total cholesterol levels (m) of ob/ob and m/m;Ob mice fed CD (n = 8 for each group). WT, wild type; m/m, Lgr4m/m; Ob, ob/ob mice; m/m;Ob, Lgr4/leptin double mutant mice. TG, triglycerides; TC, total cholesterol. *,p<0.05;**,p<0.01;***,p<0.001. Error bars, s.e.m.

Supplementary Figure 2 Increased energy expenditure in Lgr4/leptin double mutant mice.

(a-d) Food intake (a, b) and physical activity (c, d) of the two groups was measured in a 24 h period (a, c, 24 h period; b, d, the average quantification for 12 h light and 12 h dark in a and c, respectively) (n = 8 for each group). (e, f) 24 h energy expenditure was compared between the two groups (e, energy expenditure per mouse was plotted against lean mass; f, the adjusted means of energy expenditure in the two groups analyzed by ANCOVA with fat mass and lean mass as two covariates, n = 8, P = 0.1). (g-j) O2 consumption (g, h) and CO2 production (i, j) was recorded during a 24 h period (g, i, 24 h period; h, j, average of light and dark time, respectively) (n = 8 for each group). WT, wild type; m/m, Lgr4m/m; Ob, ob/ob mice; m/m;Ob, Lgr4/leptin double mutant mice. *,p<0.05;**,p<0.01;***,p<0.001. Error bars, s.e.m.

Supplementary Figure 3 Unchanged BAT phenotypes in Lgr4m/m mice.

Ablation of Lgr4 induces white-to-brown fat transition but does not affect the interscapular BAT. (a) Hematoxylin and eosin staining of BAT in wild-type and Lgr4m/m mice. Scale bar, 100 μm. (b) Electron microscopy of BAT in wild-type and Lgr4m/m mice. Scale bar, 1,000 nm. (c, d) Mitochondrion number of BAT between wild-type and Lgr4m/m mice determined by the normalized 16s rRNA level to hexokinase 2 level (c) and the normalized cytochrome b level to gapdh level (d). Hexo, hexokinase 2 gene; Cyt b, cytochrome b gene. (e) Protein levels of BAT-related genes in wild-type and Lgr4m/m mice under CD (left panel) or HFD (right panel). Uncropped data are depicted in Supplementary Fig. S7b. WT, wild-type mice; m/m, Lgr4m/m mice. Error bars, s.e.m.

Supplementary Figure 4 Ablation of Lgr4 induces white-to-brown fat transition.

(a) Electron microscopy of eWAT in wild-type and Lgr4m/m mice. Wild-type BAT was used as the reference. Scale bar, 10 μm. (b) Hematoxylin and eosin staining of eWAT in wild-type and Lgr4m/m mice; 4-month-old wild-type and mutant mice were treated under normal conditions or cold room for 7 days, or isoprenaline injection (0.75 mg/kg body weight) for 10 days. Scale bar, 100 μm. (c, d) Representative haematoxylin and eosin staining (scale bar, 100 μm) (c) and electron microscopy (scale bar, 5 μm). (d) of eWAT in Ob and m/m;Ob mice under normal conditions. (e) Immunohistochemical staining of CD137 and TMEM26 in eWAT of wild-type and Lgr4m/m mice under isoprenaline treatment for 10 days (scale bar, 50 μm). (f) Protein levels of BAT-related genes in eWAT and iWAT of wild-type and Lgr4m/m mice under cold room stress. eWAT, left panel, iWAT, right panel. Uncropped data are depicted in Supplementary Fig. S7c. (g-l) Plasma levels of thyroid hormones (g, h) and principal catecholamines (i, j), and 12 h urinary catecholamine excretion normalized to body weight (k, l) in wild-type and Lgr4m/m mice (n = 6-12 for each group). WT, wild-type mice; m/m, Lgr4m/m mice; Ob, ob/ob mice; m/m;Ob, Lgr4/leptin double mutant mice. *,p<0.05;**,p<0.01;***,p<0.001. Error bars, s.e.m.

Supplementary Figure 5 Ablation of Lgr4 promotes the differentiation of eWAT SVF to brown adipocyte in vitro.

(a, b) Representative phase (a) and Oil Red O staining images (b) of the fully differentiated eWAT SVF with brown adipocyte induction under microscopy. Scale bar, 50 μm. (c) Relative mRNA levels of beige adipocyte related genes in the differentiated SVF cells from the eWAT of wild-type and Lgr4m/m mice (n = 3-5). Source data are provided in Supplementary Table S5. (d) Gene set enrichment analysis (GSEA). Black columns indicated 214 genes significantly down-regulated in the fully differentiated Lgr4m/m SVF, which were involved in cell adhesion, angiogenesis, cell cycle, cell-matrix adhesion, negative regulation of cell proliferation, actin filament bundle assembly, collagen fibril organization, cell shape regulation, vascular endothelial growth factor receptor signaling pathway. Differentially expressed genes were ranked according to the folds of Lgr4m/m adipocytes vs. wild-type adipocytes. d also referred to Supplementary Table S2. (e) Basal and insulin-stimulated 2-deoxyglucose uptake of the differentiated SVF cells (n = 3-4 for each group). (f) Relative mRNA levels of WAT selective markers in the differentiated SVF cells from wild-type and Lgr4m/m mice after eight-day differentiation with classical white adipocyte induction cocktails (n = 3-4 for each group). (g) Relative mRNA levels of BAT related genes in the differentiated SVF cells from the eWAT of wild-type and Lgr4m/m mice after isoprenaline injection. Wild-type and Lgr4m/m mice were treated with isoprenaline (0.75mg/kg body weight) for 10 days before isolating the SVF, which were then differentiated into brown adipocytes. (n = 6 for wild type and n = 3 for m/m). For e-g, source data are provided in Supplementary Table S5. (h) Isolation of the PDGFRα+ cells from the eWAT SVF of wild-type and Lgr4m/m mice by FACS. Isotype IgG was used as a negative control. WT, wild-type mice; m/m, Lgr4m/m mice. *,p<0.05;**,p<0.01;***,p<0.001. Error bars, s.e.m.

Supplementary Figure 6 LGR4 regulates Rb expression.

(a) Relative mRNA levels of the indicated genes in eWAT SVF of wild-type and Lgr4m/m mice (n = 5-7 for wild type and n = 4 for m/m). Source data are provided in Supplementary Table S5. (b) Rb mRNA levels in eWAT of wild-type and Lgr4m/m mice under cold room stimulation and isoprenaline treatment for 7 days and 10 days respectively. (c) Relative Rb mRNA levels after knockdown of Lgr4 in C3H10T1/2 cells using its SiRNA (n = 4). Source data are provided in Supplementary Table S5. (d) The transcriptional activity of the indicated truncated Rb promoters was compared (n = 3). (e) Rb mRNA levels in wild-type SVF and Lgr4 mutant SVF infected with lentiviral vector or lentiviral Rb construct (n = 3). (f) The Lgr4 mRNA levels in wild-type SVF and Lgr4 mutant SVF infected with lentiviral vector or lentiviral LGR4 construct (n = 3). For d-f, source data are provided in Supplementary Table S5. (g) The protein levels of cytoplasmic and nuclear β-catenin in eWAT of wild-type and Lgr4m/m mice. α-tubulin was used as the loading control for cytoplasmic proteins; Lamin B was used as the loading control for nuclear proteins. Uncropped data are depicted in Supplementary Fig. S7e. WT, wild-type mice; m/m, Lgr4m/m mice. Trc, Truncated; mRb, mouse Rb; Ctrl, control. LV, lentiviral vector. *,p<0.05;**,p<0.01;***,p<0.001. Error bars, s.e.m.

Supplementary Figure 7 Full scans of western immunoblotting.

(a) Related to Fig. 3i, (b) Related to Supplementary Fig. 3e, (c) Related to Supplementary Fig. 4f, (d) Related to Fig. 5b (e) Related to Supplementary Fig. 6g. NC, normal condition, CR, cold room stimulation, ISO, isoprenaline treatment, HFD, high-fat diet. WT, wild-type, m/m, Lgr4 mutant.

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Wang, J., Liu, R., Wang, F. et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol 15, 1455–1463 (2013). https://doi.org/10.1038/ncb2867

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