Insulin signaling and copper homeostasis are functionally linked in 3T3‐L1 adipocytes (992.2)

Abstract

Copper is an essential element for human growth and development. Abnormal copper metabolism is associated with severe and potentially lethal disorders. Previous studies of copper misbalance in the animal model of Wilson’s disease have shown that copper levels influence cholesterol and triglyceride content in tissues. To understand the mechanisms connecting copper and lipid metabolism, we characterized copper homeostasis in 3T3‐L1 adipocytes upon differentiation and insulin signaling. We show that during adipogenesis copper uptake is upregulated 2‐3 fold. Protein levels of the copper‐transporting ATP7A also increase, presumably to facilitate copper delivery to semicarbazide‐sensitive amine oxidase (SSAO), a copper‐containing enzyme that exerts an insulin‐like effect and is highly upregulated in differentiated adipocytes. Both copper depletion and copper elevation inhibit SSAO’s activity, suggesting a fine‐tuned regulation of this enzyme by the metal. In turn, SSAO’s substrates and product regulate ATP7A localization in cells triggering trafficking form the trans‐Golgi network to vesicles. In response to insulin, copper uptake remains unchanged, whereas ATP7A traffics to the plasma membrane and vesicles indicating insulin‐dependent redistribution of intracellular copper pools. Altogether, our data revealed a novel metabolic connection between copper homeostasis and insulin signaling in differentiated adipocytes.* Equal contributionGrant Funding Source: NIH R01 GM101502