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

Nature Cell Biology volume 15, pages 14551463 (2013) | Download Citation


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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  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

    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).

  7. 7.

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

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

    , , & Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).

  12. 12.

    , , & In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).

  13. 13.

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

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

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

  22. 22.

    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).

  23. 23.

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

  24. 24.

    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).

  25. 25.

    , , , & 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).

  26. 26.

    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).

  27. 27.

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

  28. 28.

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

  29. 29.

    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).

  30. 30.

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

  31. 31.

    , & 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).

  32. 32.

    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).

  33. 33.

    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).

  34. 34.

    , , , & Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea. J. Assist. Reprod. Genet. 27, 317–326 (2010).

  35. 35.

    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).

  36. 36.

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

  37. 37.

    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).

  38. 38.

    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).

  39. 39.

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

  40. 40.

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

  41. 41.

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

  42. 42.

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

  43. 43.

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

  44. 44.

    & 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).

  45. 45.

    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).

  46. 46.

    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).

  47. 47.

    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).

  48. 48.

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

  49. 49.

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

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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.

Author information

Author notes

    • Jiqiu Wang
    • , Ruixin Liu
    •  & Feng Wang

    These authors contributed equally to this work


  1. Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Key Laboratory for Endocrine Tumors and E-Institute of Shanghai Universities, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China

    • Jiqiu Wang
    • , Ruixin Liu
    • , Jie Hong
    • , Xiaoying Li
    • , Maopei Chen
    • , Yingying Ke
    • , Xianfeng Zhang
    • , Qinyun Ma
    • , Rui Wang
    • , Juan Shi
    • , Bin Cui
    • , Weiqiong Gu
    • , Yifei Zhang
    • , Zhiguo Zhang
    • , Weiqing Wang
    •  & Guang Ning
  2. Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Shanghai 200025, China

    • Feng Wang
    •  & Guang Ning
  3. Genomic Medicine and Diabetes Research, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, Texas 77030, USA

    • Xuefeng Xia
  4. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA

    • Mingyao Liu


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Guang Ning.

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