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Copper in Adipocyte Functions and Energy Homeostasis
Adipocytes play critical roles in metabolism by storing excess energy and utilizing fat through lipolysis and thermogenesis. Copper is an essential micronutrient for mammals in energy generation, thermogenic signaling, and lipid metabolism; nevertheless, uptake, distribution, and utilization of copper to support the adipocyte functions and implication of copper dysregulation in adipocyte-dependent metabolic disorders remain elusive. The long-term goal of this research project is to discover copper homeostasis in adipocytes with their metabolic activities and reveal the impacts of copper dysregulation in adipocytes on energy metabolism and metabolic diseases. To determine the regulation of copper as a function of adipocyte activities, we assessed copper homeostasis markers in the mice housed at a cold temperature demanding thermogenic energy expenditure or fed a high-fat diet (HFD) supplying excess energy. Our data demonstrated that adipocyte-dependent non-shivering thermogenesis increased the demand for copper in white adipose tissues (WAT), reflecting the recruitment of beige adipocytes possessing higher amounts of mitochondria that sequester copper. The reduced hepatic copper content suggests a redistribution of copper from the liver to adipose tissues. Conversely, the intake of a high-fat diet increased copper availability in the cytosol of WAT. We next generated and characterized a mouse line where the copper transporter 1 (Ctr1) gene encoding a high-affinity copper importer was deleted in adipocytes. The tissue copper levels and biomarkers revealed that CTR1 imports a significant portion of copper in the fat tissues. Ctr1 gene knockout mice tolerated copper limitation in the recommended/optimal growing conditions. Interestingly, Ctr1 gene knockout increased beige adipocyte recruitment and uncoupling protein 1 (UCP1) expression in the inguinal WAT, suggesting activation of thermogenic signaling pathways. When Ctr1-deficient mice were on HFD, the mice manifested reduced adipose tissue weight, increased energy expenditure, improved glucose homeostasis, and less hepatic fat accumulation. Indirect calorimetry analysis revealed a higher basal metabolism in the mice. Collectively, our study revealed a previously unrecognized relationship between copper and adipocyte-dependent macronutrient metabolism. These results are anticipated to advance our ability to combat obesity and metabolic diseases.
Zhao, Miaoyun, "Copper in Adipocyte Functions and Energy Homeostasis" (2021). ETD collection for University of Nebraska-Lincoln. AAI28866038.