Redox-metabolic synergy - a backbone interface for adipocentric approach to metabolic diseases

Abstract

Understanding mechanisms that enable/restrict the metabolic plasticity of adipose tissue (AT) is crucial for reducing the global burden of obesity and metabolic diseases. We consistently showed that metabolic reprogramming of adipose tissue is inevitably tied to redox reprogramming in numerous physiological (cold re-acclimation, hibernation) and pathophysiological states (obesity, metabolic syndrome, diabetes, cancer). Cumulative evidence suggests that AT's redox-metabolic regulatory feedback loop is under pressure in overnutrition states. Namely, an increase in glucose and fatty acid flux via adipocytes shifts the balance of redox systems (NAD(P)+/NAD(P)H, thiol - S-/SH and glutathione - GSSG/GSH, antioxidant/prooxidant enzymes), thus increasing the levels of reactive oxygen and nitrogen species (RO(N)S). When produced in a controlled manner, RO(N)S regulate the activities of numerous proteins increasing the lipid buffering capacity. Persistent nutritional overload, however, and consequent oxidative pressure may at any moment exceed the antioxidant capacity of the adipocyte leading to irreversible damage of proteins and other biomolecules, impairing metabolic and endocrine function of AT. Understanding how the "redox milieu" limits AT capacity for lipid storage and oxidation is vital for designing treatment strategies in obesity. Our results show that investigating specific panels of redox biomarkers can clearly "mark" AT depots with disrupted lipid buffering capacity, thus identifying the risk of metabolic syndrome in obesity. Besides, our research aims to target the AT contribution to metabolic diseases such as diabetes, atherosclerosis, and cancer by shifting the AT redox homeostasis. We showed that setting the "catabolic redox milieu" in AT by targeting nitric oxide (NO) and glutathione (GSH) signaling can "ignite" AT by inducing a brown AT-like thermogenic phenotype. Such redox-based approaches (NO supplementation, GSH depletion) show great therapeutic potential as an alternative to natural stimuli such as cold exposure or adrenergic stimulation. In summary, obesity and related metabolic diseases are redox diseases of AT that could be targeted by advancing selective AT-specific redox-based approaches. Investigations partially Funded by Science Fund of the Republic of Serbia, Program for Excellent Projects of Young Researchers, grant # 6066747