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

Abstract

Sugar-induced metabolic imbalances are a major health problem since an excessive consumption of saccharides has been linked to greater obesity rates at a global level. Sucrose, a disaccharide composed of 50% glucose and 50% fructose, is commonly used in the food industry and found in a range of fast, restaurant, and processed foods. Herein, we investigated the effects of a TRPC4/TRPC5 blocker, ML204, in the metabolic imbalances triggered by early exposure to sucrose-enriched diet in mice. TRPC4 and TRPC5 belong to the family of non-selective Ca+2 channels known as transient receptor potential channels. High-sucrose (HS)-fed animals with hyperglycaemia and dyslipidaemia, were accompanied by increased body mass index. mesenteric adipose tissue accumulation with larger diameter cells and hepatic steatosis in comparison to those fed normal diet. HS mice also exhibited enhanced adipose, liver, and pancreas TNFα and VEGF levels. ML204 exacerbated hyperglycaemia, dyslipidaemia, fat tissue deposition, hepatic steatosis, and adipose tissue and liver TNFα in HS-fed mice. Normal mice treated with the blocker had greater hepatic steatosis and adipose tissue cell numbers/diameter than those receiving vehicle, but showed no significant changes in tissue inflammation, glucose, and lipid levels. The results indicate that TRPC4/TRPC5 protect against the metabolic imbalances caused by HS ingestion.

High Sucrose Diet-Induced Subunit I Tyrosine 304 Phosphorylation of Cytochrome c Oxidase Leads to Liver Mitochondrial Respiratory Dysfunction in the Cohen Diabetic Rat Model

“…It has been shown that mice subjected to a high-sucrose diet display signs of inflammation in their adipose tissue and liver, marked by elevated levels of pro-inflammatory cytokine TNFα [37], a cytokine associated with adipocyte enlargement, fat accumulation, insulin resistance, and elevated blood sugar levels. Previously, we discovered that TNFα significantly decreased CcO activity in mouse liver tissue through downstream phosphorylation of Y304 residue of CcO catalytic subunit I, resulting in a sharp decline in mitochondrial membrane potential and a reduction in cellular ATP levels [19].…”

TRPC absence induces pro-inflammatory macrophage polarization to promote obesity and exacerbate colorectal cancer

“…Additionally, the TRPC3 channel enhances sensitivity in gustatory perception of dietary lipids, potentially influencing preferences for lipid intake and thereby affecting the occurrence of obesity ( Murtaza et al, 2021 ). On the other hand, TRPC4/TRPC5 has been shown to protect against hyperglycemia and dyslipidemia caused by a high-sucrose diet ( Araujo et al, 2023 ). However, interestingly, deletion of TRPC5 in the central amygdala has been shown to counteract obesity induced by a high-fat diet through an increase in sympathetic innervation ( Ma et al, 2022 ).…”