Zinc homeostasis and redox alterations in obesity

Abstract

Impairment of both cellular zinc and redox homeostasis is a feature of several chronic diseases, including obesity. A significant two-way interaction exists between redox metabolism and the relatively redox-inert zinc ion. Redox metabolism critically influences zinc homeostasis and controls its cellular availability for various cellular functions by regulating zinc exchange from/to zinc-binding proteins. Zinc can regulate redox metabolism and exhibits multiple pro-antioxidant properties. On the other hand, even minor disturbances in zinc status and zinc homeostasis affect systemic and cellular redox homeostasis. At the cellular level, zinc homeostasis is regulated by a multi-layered machinery consisting of zinc-binding molecules, zinc sensors, and two selective families of zinc transporters, the Zinc Transporter (ZnT) and Zrt, Irt-like protein (ZIP). In the present review, we summarize the current state of knowledge on the role of the mutual interaction between zinc and redox homeostasis in physiology and pathophysiology, pointing to the role of zinc in the alterations responsible for redox stress in obesity. Since zinc transporters primarily control zinc homeostasis, we describe how changes in the expression and activity of these zinc-regulating proteins are associated with obesity.

Keywords: ZIP; ZnT; buffering; metallothioneins; oxidative stress; zinc status.

Figure 1

Overview of biological functions of zinc in living organisms. Created with BioRender.com.

Figure 2

Mechanisms of pro-antioxidant actions of zinc in living organisms. (A) Zinc stabilizes the cell membrane by competing with redox-active metals and preventing the formation of highly oxidant lipid peroxides; (B) NO- and ROS-induced zinc release from MTs helps to counteract OS through the translocation of MTF1 and NRF2 to the nucleus, which in turn activate the transcription of genes encoding MTs and antioxidant defenses; (C) SOD1 and (D) NOXs as examples of enzymes in which zinc is an essential structural component and a regulator of the activity of ROS-producing enzymes. Created with BioRender.com.

Figure 3

Zinc-dependent pathways in obesity: role of ZIPs and ZnTs. (A) Localization (a) and role of Zip14 in the SAT (b) and liver (c); (B) Zip7 functional role in the Golgi apparatus of muscle, (C) Zip13 and (D) ZnT7 functional role in the Golgi apparatus of SAT; (E) ZnT8 role in the regulation of insulin release (a) and insulin sensitivity (b, c). Created with BioRender.com.