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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

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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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.

Author information

Author notes

    • Jiqiu Wang
    • , Ruixin Liu
    •  & Feng Wang

    These authors contributed equally to this work

Affiliations

  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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Guang Ning.

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https://doi.org/10.1038/ncb2867

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