Abstract
BackgroundMany tissues play an important role in metabolic homeostasis and the development of diabetes and obesity. We hypothesized that the circulating redox metabolome is a master metabolic regulatory system that impacts all organs and modulates reactive oxygen species (ROS) production, lipid peroxidation, energy production and changes in lipid turnover in many cells including adipocytes.MethodsDifferentiated human preadipocytes were exposed to the redox couples, lactate (L) and pyruvate (P), β–hydroxybutyrate (βOHB) and acetoacetate (Acoc), and the thiol-disulfides cysteine/ cystine (Cys/CySS) and GSH/GSSG for 1.5–4 hours. ROS measurements were done with CM-H2DCFDA. Lipid peroxidation (LPO) was assessed by a modification of the thiobarbituric acid method. Lipolysis was measured as glycerol release. Lipid synthesis was measured as 14C-glucose incorporated into lipid. Respiration was assessed using the SeaHorse XF24 analyzer and the proton leak was determined from the difference in respiration with oligomycin and antimycin A.ResultsMetabolites with increasing oxidation potentials (GSSG, CySS, Acoc) increased adipocyte ROS. In contrast, P caused a decrease in ROS compared with L. Acoc also induced a significant increase in both LPO and lipid synthesis. L and Acoc increased lipolysis. βOHB increased respiration, mainly due to an increased proton leak. GSSG, when present throughout 14 days of differentiation significantly increased fat accumulation, but not when added later.ConclusionsWe demonstrated that in human adipocytes changes in the external redox state impacted ROS production, LPO, energy efficiency, lipid handling, and differentiation. A more oxidized state generally led to increased ROS, LPO and lipid turnover and more reduction led to increased respiration and a proton leak. However, not all of the redox couples were the same suggesting compartmentalization. These data are consistent with the concept of the circulating redox metabolome as a master metabolic regulatory system.
Highlights
It is well established that oxidation-reduction reactions exist in all cells and that they play a major role in human health and disease
We demonstrated that in human adipocytes changes in the external redox state impacted reactive oxygen species (ROS) production, Lipid peroxidation (LPO), energy efficiency, lipid handling, and differentiation
A more oxidized state generally led to increased ROS, LPO and lipid turnover and more reduction led to increased respiration and a proton leak
Summary
It is well established that oxidation-reduction (redox) reactions exist in all cells and that they play a major role in human health and disease. When produced in large quantities, ROS have the potential to cause a number of deleterious events: but in small quantities, play a role in signaling. Both intracellular and extracellular thiol redox cycles play central roles in maintaining ROS/redox balance [6,7,8]. The circulating redox metabolites are produced by cells and may be sensed by all the tissues of the body These couples include: the thiol (SH/SS) reflected in the cysteine/cystine (Cys/CySS), the reduced and oxidized gluthathione (GSH/GSSG), and the pyridine nucleotides NADPH/NADP and NADH/ NAD. We hypothesized that the circulating redox metabolome is a master metabolic regulatory system that impacts all organs and modulates reactive oxygen species (ROS) production, lipid peroxidation, energy production and changes in lipid turnover in many cells including adipocytes
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