Adipocyte-specific disruption of ATPase copper transporting α in mice accelerates lipoatrophy
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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.
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).
KeywordsAdipose tissues ATP7A Copper Insulin resistance Lipoatrophy
Adipose triglyceride lipase
ATPase copper-transporting α
Brown adipose tissue
CCAAT enhancer binding protein α
Gonadal white adipose tissue
Phosphorylated histone H2AX
Inductively coupled plasma MS
Perinephric white adipose tissue
Cyclin-dependent kinase inhibitor 1A
Tumour protein p53
Peroxisome proliferator activated receptor γ
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.
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.
- 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
- 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
- 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