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Diabetologia

pp 1–14 | Cite as

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
Article
  • 164 Downloads

Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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 (http://bigd.big.ac.cn/gsa).

Keywords

Adipose tissues ATP7A Copper Insulin resistance Lipoatrophy 

Abbreviations

ADRB3

Adrenoceptor β3

ASKO

Adipocyte-specific Atp7a-knockout

ATGL

Adipose triglyceride lipase

ATP7A

ATPase copper-transporting α

BAT

Brown adipose tissue

CEBPα

CCAAT enhancer binding protein α

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

gWAT

Gonadal white adipose tissue

γ-H2AX

Phosphorylated histone H2AX

HFD

High-fat diet

HSL

Hormone-sensitive lipase

ICP-MS

Inductively coupled plasma MS

pWAT

Perinephric white adipose tissue

p21

Cyclin-dependent kinase inhibitor 1A

p53

Tumour protein p53

p563HSL

Phospho-HSL Ser563

p565HSL

Phospho-HSL Ser565

PPARγ

Peroxisome proliferator activated receptor γ

qPCR

Quantitative PCR

RNA-Seq

RNA sequencing

sWAT

Subcutaneous white adipose tissue

TEM

Transmission electron microscopy

WAT

White adipose tissue

WT

Wild-type

Notes

Acknowledgements

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.

Funding

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)

References

  1. 1.
    Kardos J, Héja L, Simon Á, Jablonkai I, Kovács R, Jemnitz K (2018) Copper signalling: causes and consequences. Cell Commun Signal 16(1):71.  https://doi.org/10.1186/s12964-018-0277-3 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kodama H, Fujisawa C (2009) Copper metabolism and inherited copper transport disorders: molecular mechanisms, screening, and treatment. Metallomics 1(1):42–52.  https://doi.org/10.1039/B816011M CrossRefGoogle Scholar
  3. 3.
    Morrell A, Tallino S, Yu L, Burkhead JL (2017) The role of insufficient copper in lipid synthesis and fatty-liver disease. IUBMB Life 69(4):263–270.  https://doi.org/10.1002/iub.1613 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Aigner E, Strasser M, Haufe H et al (2010) A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am J Gastroenterol 105(9):1978–1985.  https://doi.org/10.1038/ajg.2010.170 CrossRefPubMedGoogle Scholar
  5. 5.
    Feldman A, Aigner E, Weghuber D, Paulmichl K (2015) The potential role of iron and copper in pediatric obesity and nonalcoholic fatty liver disease. Biomed Res Int. www.hindawi.com/journals/bmri/2015/287401/. Accessed 7 Jan 2019 2015:1–7.  https://doi.org/10.1155/2015/287401 CrossRefGoogle Scholar
  6. 6.
    Klevay LM (2011) Is the Western diet adequate in copper? J Trace Elem Med Biol 25(4):204–212.  https://doi.org/10.1016/j.jtemb.2011.08.146 CrossRefPubMedGoogle Scholar
  7. 7.
    Al-Othman AA, Rosenstein F, Lei KY (1992) Copper deficiency alters plasma pool size, percent composition and concentration of lipoprotein components in rats. J Nutr 122(6):1199–1204.  https://doi.org/10.1093/jn/122.6.1199 CrossRefPubMedGoogle Scholar
  8. 8.
    Al-Othman AA, Rosenstein F, Lei KY (1993) Copper deficiency increases in vivo hepatic synthesis of fatty acids, triacylglycerols, and phospholipids in rats. Proc Soc Exp Biol Med 204(1):97–103.  https://doi.org/10.3181/00379727-204-43640 CrossRefPubMedGoogle Scholar
  9. 9.
    Song M, Vos MB, McClain CJ (2018) Copper-fructose interactions: a novel mechanism in the pathogenesis of NAFLD. Nutrients 10(11).  https://doi.org/10.3390/nu10111815 CrossRefGoogle Scholar
  10. 10.
    Levy E, Brunet S, Alvarez F et al (2007) Abnormal hepatobiliary and circulating lipid metabolism in the Long-Evans Cinnamon rat model of Wilson’s disease. Life Sci 80(16):1472–1483.  https://doi.org/10.1016/j.lfs.2007.01.017 CrossRefPubMedGoogle Scholar
  11. 11.
    Seessle J, Gohdes A, Gotthardt DN et al (2011) Alterations of lipid metabolism in Wilson disease. Lipids Health Dis 10(1):83.  https://doi.org/10.1186/1476-511X-10-83 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hamilton JP, Koganti L, Muchenditsi A et al (2016) Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B−/− (Wilson disease) mice. Hepatology 63(6):1828–1841.  https://doi.org/10.1002/hep.28406 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tan X-Y, Luo Z, Liu X, Xie C-X (2011) Dietary copper requirement of juvenile yellow catfish Pelteobagrus fulvidraco. Aquac Nutr 17(2):170–176.  https://doi.org/10.1111/j.1365-2095.2009.00720.x CrossRefGoogle Scholar
  14. 14.
    Chen Q-L, Luo Z, Wu K et al (2015) Differential effects of dietary copper deficiency and excess on lipid metabolism in yellow catfish Pelteobagrus fulvidraco. Comp Biochem Physiol B: Biochem Mol Biol 184:19–28.  https://doi.org/10.1016/j.cbpb.2015.02.004 CrossRefGoogle Scholar
  15. 15.
    Engle TE (2011) Copper and lipid metabolism in beef cattle: A review. J Anim Sci 89(2):591–596.  https://doi.org/10.2527/jas.2010-3395 CrossRefPubMedGoogle Scholar
  16. 16.
    Scherer PE (2006) Adipose tissue from lipid storage compartment to endocrine organ. Diabetes 55(6):1537–1545.  https://doi.org/10.2337/db06-0263 CrossRefPubMedGoogle Scholar
  17. 17.
    Liu L, Jiang Q, Wang X et al (2014) Adipose-specific knockout of Seipin/Bscl2 results in progressive lipodystrophy. Diabetes 63(7):2320–2331.  https://doi.org/10.2337/db13-0729 CrossRefPubMedGoogle Scholar
  18. 18.
    Softic S, Boucher J, Solheim MH et al (2016) Lipodystrophy due to adipose tissue-specific insulin receptor knockout results in progressive NAFLD. Diabetes 65(8):2187–2200.  https://doi.org/10.2337/db16-0213 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Guilherme A, Virbasius JV, Puri V, Czech MP (2008) Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 9(5):367–377.  https://doi.org/10.1038/nrm2391 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hajer GR, van Haeften TW, Visseren FLJ (2008) Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 29(24):2959–2971.  https://doi.org/10.1093/eurheartj/ehn387 CrossRefPubMedGoogle Scholar
  21. 21.
    Rodríguez JP, Ríos S, González M (2002) Modulation of the proliferation and differentiation of human mesenchymal stem cells by copper. J Cell Biochem 85(1):92–100.  https://doi.org/10.1002/jcb.10111 CrossRefPubMedGoogle Scholar
  22. 22.
    Krishnamoorthy L, Cotruvo JA Jr et al (2016) Copper regulates cyclic AMP-dependent lipolysis. Nat Chem Biol 12(8):586–592.  https://doi.org/10.1038/nchembio.2098 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yang H, Ralle M, Wolfgang MJ et al (2018) Copper-dependent amino oxidase 3 governs selection of metabolic fuels in adipocytes. PLoS Biol 16(9):e2006519.  https://doi.org/10.1371/journal.pbio.2006519 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang Y, Zhu S, Hodgkinson V et al (2012) Maternofetal and neonatal copper requirements revealed by enterocyte-specific deletion of the Menkes disease protein. Am J Physiol Gastrointest Liver Physiol 303(11):G1236–G1244.  https://doi.org/10.1152/ajpgi.00339.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ladomersky E, Khan A, Shanbhag V et al (2017) Host and pathogen copper-transporting P-type ATPases function antagonistically during salmonella infection. Infect Immun 85(9):e00351–e00317.  https://doi.org/10.1128/IAI.00351-17 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hodgkinson VL, Dale JM, Garcia ML et al (2015) X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron. J Pathol 236(2):241–250.  https://doi.org/10.1002/path.4511 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Qin Z, Konaniah ES, Neltner B, Nemenoff RA, Hui DY, Weintraub NL (2010) Participation of ATP7A in macrophage mediated oxidation of LDL. J Lipid Res 51(6):1471–1477.  https://doi.org/10.1194/jlr.M003426 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang C, Liang X, Tao C et al (2017) Induction of copper and iron in acute cold-stimulated brown adipose tissues. Biochem Biophys Res Commun 488(3):496–500.  https://doi.org/10.1016/j.bbrc.2017.05.073 CrossRefPubMedGoogle Scholar
  29. 29.
    Wang Y, Zhu S, Weisman GA, Gitlin JD, Petris MJ (2012) Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis. PLoS One 7(8):e43039.  https://doi.org/10.1371/journal.pone.0043039 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yuan X, Wei G, You Y et al (2016) Rutin ameliorates obesity through brown fat activation. FASEB J 31(1):333–345.  https://doi.org/10.1096/fj.201600459RR CrossRefPubMedGoogle Scholar
  31. 31.
    Yang X, Lu X, Lombès M et al (2010) The G0/G1 switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab 11(3):194–205.  https://doi.org/10.1016/j.cmet.2010.02.003 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lin J, Cao C, Tao C et al (2017) Cold adaptation in pigs depends on UCP3 in beige adipocytes. J Mol Cell Biol 9(5):364–375.  https://doi.org/10.1093/jmcb/mjx018 CrossRefPubMedGoogle Scholar
  33. 33.
    Cortés VA, Curtis DE, Sukumaran S et al (2009) Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metab 9(2):165–176.  https://doi.org/10.1016/j.cmet.2009.01.002 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mcilroy GD, Suchacki K, Roelofs AJ et al (2018) Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease. Mol Metab 10:55–65.  https://doi.org/10.1016/j.molmet.2018.01.019 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zhou L, Park S-Y, Xu L et al (2015) Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice. Nat Commun 6(1):5949.  https://doi.org/10.1038/ncomms6949 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Linder MC (2012) The relationship of copper to DNA damage and damage prevention in humans. Mutat Res Fundam Mol Mech Mutagen 733(1):83–91.  https://doi.org/10.1016/j.mrfmmm.2012.03.010 CrossRefGoogle Scholar
  37. 37.
    Minamino T, Orimo M, Shimizu I et al (2009) A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 15(9):1082–1087.  https://doi.org/10.1038/nm.2014 CrossRefPubMedGoogle Scholar
  38. 38.
    Stout MB, Justice JN, Nicklas BJ, Kirkland JL (2016) Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology 32(1):9–19.  https://doi.org/10.1152/physiol.00012.2016 CrossRefPubMedCentralGoogle Scholar
  39. 39.
    Vergoni B, Cornejo P-J, Gilleron J et al (2016) DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes. Diabetes 65(10):3062–3074.  https://doi.org/10.2337/db16-0014 CrossRefPubMedGoogle Scholar
  40. 40.
    Burkhead JL, Lutsenko S (2013) The role of copper as a modifier of lipid metabolism. Available from www.intechopen.com/books/lipid-metabolism/the-role-of-copper-as-a-modifier-of-lipid-metabolism.  https://doi.org/10.5772/51819 Google Scholar

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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