Adipocyte-specific disruption of ATPase copper transporting α in mice accelerates lipoatrophy
Adipocyte-specific disruption of ATPase copper transporting α in mice accelerates lipoatrophy
复制标题
小鼠脂肪细胞特异性破坏 ATP 酶铜转运 α 加速脂肪萎缩
DOI：
10.1007/s00125-019-4966-2
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发表时间：
2019-12-01
期刊：
影响因子：
8.2
通讯作者：
Wang, Yanfang
中科院分区：
文献类型：
--
作者：
Tao, Cong;Wang, Yajun;Wang, Yanfang
Aims/hypothesis ATPase copper transporting alpha (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.
