An Overview of the TRP-Oxidative Stress Axis in Metabolic Syndrome: Insights for Novel Therapeutic Approaches

Abstract

Metabolic syndrome (MS) is a complex pathology characterized by visceral adiposity, insulin resistance, arterial hypertension, and dyslipidaemia. It has become a global epidemic associated with increased consumption of high-calorie, low-fibre food and sedentary habits. Some of its underlying mechanisms have been identified, with hypoadiponectinemia, inflammation and oxidative stress as important factors for MS establishment and progression. Alterations in adipokine levels may favour glucotoxicity and lipotoxicity which, in turn, contribute to inflammation and cellular stress responses within the adipose, pancreatic and liver tissues, in addition to hepatic steatosis. The multiple mechanisms of MS make its clinical management difficult, involving both non-pharmacological and pharmacological interventions. Transient receptor potential (TRP) channels are non-selective calcium channels involved in a plethora of physiological events, including energy balance, inflammation and oxidative stress. Evidence from animal models of disease has contributed to identify their specific contributions to MS and may help to tailor clinical trials for the disease. In this context, the oxidative stress sensors TRPV1, TRPA1 and TRPC5, play major roles in regulating inflammatory responses, thermogenesis and energy expenditure. Here, the interplay between these TRP channels and oxidative stress in MS is discussed in the light of novel therapies to treat this syndrome.

Analysis of the Effect of the TRPC4/TRPC5 Blocker, ML204, in Sucrose-Induced Metabolic Imbalance

“…Inflammation is an important event that contributes to metabolic imbalances; thus, tumour necrosis factor α (TNFα) and vascular endothelial growth factor (VEGF) levels (inflammatory mediators involved in obesity and glycaemia control (for review see: [ 33 , 40 ])) were evaluated in adipose tissue, liver, and pancreas samples obtained from animals fed either a standard or HS diet. HS diet-fed mice led to a greater release of these inflammatory mediators in adipose tissue and liver samples in comparison with those receiving standard diet, an effect which was further enhanced by ML204 injection ( Figure 4 A–D; p < 0.05).…”

“…Also in agreement, HS significantly increased BMI, hyperglycaemia, mesenteric fat deposition, glucose tolerance, hypercholesterolemia, and NAS score in comparison with mice receiving a standard diet. In addition, HS-fed mice presented with adipose tissue and liver inflammation characterised by increased levels of TNFα, a cytokine involved in adipocyte hypertrophy, fat deposition, insulin resistance, and hyperglycaemia (for review see: [ 33 ]). Higher VEGF levels were also noted in both liver and adipose tissue samples from HS mice.…”

“…On the other hand, information on the involvement of TRP canonical channels 4 (TRPC4) and 5 (TRPC5) in weight and metabolic regulations remains scarce and deserves further investigation. As TRPC4 and TRPC5 can form homo- and heterotetramers between themselves and also with TRPC1, their roles in metabolic homeostasis are rather complex and have been recently discussed [ 33 ]. Interestingly, TRPC4 activation was found to modulate insulin secretion by triggering pancreatic cell depolarisation and Ca 2+ influx, and the disruption of TRPC1/TRPC5 signalling was demonstrated to result in an increased generation of adiponectin by adipocytes [ 34 , 35 ].…”

Modulation of gut microbiota and markers of metabolic syndrome in mice on cholesterol and fat enriched diet by butterfly pea flower kombucha

“…Consequently, increased ROS can decrease adiponectin, further inflammation, endothelial dysfunction, and insulin resistance. Further progression of this condition will cause hypertension, dyslipidemia, diabetes type 2, atherosclerosis, and even cancer ( Araújo et al, 2022 ). Results from this study showed that KBPF intake could suppress ROS levels (ABTS, SOD data) as well as decrease major inflammatory cytokines (TNF-α, IL-6) significantly, potentially preventing the emergence and progression of metabolic disorders in its consumers ( Fig.…”

TRP Channels in Oxidative Stress Signalling

“…Araújo et al examined the literature about the role of the TRP-oxidative stress axis in the pathogenesis and progression of metabolic syndrome, focusing on TRPV1, TRPA1 and TRPC5 in regulating the function of metabolic tissues and cells, and their connections with the central nervous system. They also discussed the potential of such TRP channels as therapeutical targets for metabolic syndrome [8].…”