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Adipocyte-specific disruption of ATPase copper transporting α in mice accelerates lipoatrophy

  • Cong Tao
  • Yajun Wang
  • Ying Zhao
  • Jianfei Pan
  • Yiping Fan
  • Xiaojuan Liang
  • Chunwei Cao
  • Jianguo Zhao
  • Michael J. Petris
  • Kui Li
  • Yanfang WangEmail author



ATPase copper transporting α (ATP7A), also known as Menkes disease protein, is a P-type ATPase that transports copper across cell membranes. The critical role of ATP7A-mediated copper homeostasis has been well recognised in various organs, such as the intestine, macrophages and the nervous system. However, the importance of adipocyte ATP7A-mediated copper homeostasis on fat metabolism is not well understood. Here, we sought to reveal the contribution of adipose ATP7A to whole-body fat metabolism in mice.


We generated adipocyte-specific Atp7a-knockout (ASKO) mice using the Cre/loxP system, with Cre expression driven by the adiponectin promoter. ASKO mice and littermate control mice were aged on a chow diet or fed with a high-fat diet (HFD); body weight, fat mass, and glucose and insulin metabolism were analysed. Histological analysis, transmission electron microscopy and RNA-sequencing (RNA-Seq) analysis of white adipose tissue (WAT) were used to understand the physiological and molecular changes associated with loss of copper homeostasis in adipocytes.


Significantly increased copper concentrations were observed in adipose tissues of ASKO mice compared with control mice. Aged or HFD-fed ASKO mice manifested a lipoatrophic phenotype characterised by a progressive generalised loss of WAT. Dysfunction of adipose tissues in these ASKO mice was confirmed by decreased levels of both serum leptin and adiponectin and increased levels of triacylglycerol and insulin. Systemic metabolism was also impaired in these mice, as evidenced by a pronounced glucose intolerance, insulin resistance and hepatic steatosis. Moreover, we demonstrate a significant induction of lipolysis and DNA-damage signalling pathways in gonadal WAT from aged and HFD-fed ASKO mice. In vitro studies suggest that copper overload is responsible for increased lipolysis and DNA damage.


Our results show a previously unappreciated role of adipocyte Atp7a in the regulation of ageing-related metabolic disease and identify new metallophysiologies in whole-body fat metabolism.

Data availability

The datasets generated during the current study are available in the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession number CRA001769 (


Adipose tissues ATP7A Copper Insulin resistance Lipoatrophy 



Adrenoceptor β3


Adipocyte-specific Atp7a-knockout


Adipose triglyceride lipase


ATPase copper-transporting α


Brown adipose tissue


CCAAT enhancer binding protein α


Glyceraldehyde-3-phosphate dehydrogenase


Gonadal white adipose tissue


Phosphorylated histone H2AX


High-fat diet


Hormone-sensitive lipase


Inductively coupled plasma MS


Perinephric white adipose tissue


Cyclin-dependent kinase inhibitor 1A


Tumour protein p53


Phospho-HSL Ser563


Phospho-HSL Ser565


Peroxisome proliferator activated receptor γ


Quantitative PCR


RNA sequencing


Subcutaneous white adipose tissue


Transmission electron microscopy


White adipose tissue





We are grateful to W. Jin from the Institute of Zoology for his generous gift of adiponectin-Cre mice and to J. Lin from the Institute of Zoology for his great help with the metabolic cage analysis.

Contribution statement

YanW and KL initiated and designed the study. CT, YajW, YZ, JP, YF and XL acquired the data. CT, JP and CC analysed the data. JZ, MJP and KL were involved in analysis and interpretation of the data. CT and YanW interpreted the data and drafted the manuscript. JZ, MJP and KL revised the article. All authors revised and approved the final version of the manuscript. YanW is responsible for the integrity of this work.


This research was funded by the Major National Scientific Research Projects (2015CB943101), the National Natural Science Foundation of China (31672387 and 31601929), the Elite Youth Programme of the Chinese Academy of Agricultural Sciences (ASTIP-IAS05) and the Fundamental Research Funds for Central Non-profit Scientific Institution (2016ywf-yb-1).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4966_MOESM1_ESM.pdf (527 kb)
ESM (PDF 526 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Cong Tao
    • 1
  • Yajun Wang
    • 1
  • Ying Zhao
    • 1
  • Jianfei Pan
    • 1
  • Yiping Fan
    • 1
  • Xiaojuan Liang
    • 1
  • Chunwei Cao
    • 2
  • Jianguo Zhao
    • 2
  • Michael J. Petris
    • 3
    • 4
    • 5
  • Kui Li
    • 1
  • Yanfang Wang
    • 1
    Email author
  1. 1.State Key Laboratory of Animal Nutrition, Institute of Animal ScienceChinese Academy of Agricultural SciencesBeijingPeople’s Republic of China
  2. 2.State Key Laboratory of Stem Cell and Reproductive Biology, Institute of ZoologyChinese Academy of SciencesBeijingPeople’s Republic of China
  3. 3.Department of BiochemistryUniversity of MissouriColumbiaUSA
  4. 4.Department of Nutrition and Exercise PhysiologyUniversity of MissouriColumbiaUSA
  5. 5.The Christopher S. Bond Life Sciences CenterUniversity of MissouriColumbiaUSA

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