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Acetate rescues defective brain-adipose metabolic network in obese Wistar rats by modulation of peroxisome proliferator-activated receptor-γ.

ABSTRACT: We investigated the hypothesis that acetate ameliorates brain-adipose metabolic dysfunction (BAMED) in high fat diet (HFD)-induced obesity, possibly by modulation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Ten-week-old male Wistar rats were randomly assigned into four groups (n = 6/group): Control, acetate and obese with or without acetate groups received vehicle (distilled water; po), acetate (200 mg/kg, po) and 40% HFD with or without acetate respectively. The treatments lasted for 12 weeks. Obese animals showed increase in body weight, visceral fat mass, insulin and triglyceride-glucose index and a reduction in insulin sensitivity. In addition, obese animals also showed increase in plasma/hypothalamic and adipose pyruvate dehydrogenase kinase-4, lactate-pyruvate ratio, malondialdehyde, γ-glutamyl transferase, and a decrease in glucose-6-phosphate dehydrogenase, glutathione, nitric oxide and PPAR-γ. HFD also elevated plasma/hypothalamic lipid and decreased adipose lipid profile, increased hypothalamic and adipose tumor necrosis factor-α, interleukin-6 and histone deacetylase (HDAC), and elevated plasma/adipose leptin. These alterations were reversed by concomitant administration of acetate. The present results demonstrate that obesity is characterized by BAMED, which is accompanied by altered HDAC/PPAR-γ. The results in addition suggest that acetate, an HDAC inhibitor rescues BAMED with consequent normalization of body weight and visceral fat mass by modulation of PPAR-γ and suppression of oxidative stress.

SUBMITTER: Olaniyi KS

PROVIDER: S-EPMC8460633 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveNuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice.MethodsA novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were administered with WO95E for 4 weeks. Insulin sensitivity, glucose tolerance, body weight, fat tissue weight, adipocyte size, morphology, energy expenditure, and expression levels of genes involved in PPARγ activity, thermogenesis/browning, and TZD-related side effects were evaluated.ResultsWO95E binds to PPARγ with high affinity and acts as a PPARγ partial agonist. WO95E inhibits PPARγ phosphorylation and regulates PPARγ phosphorylation-dependent genes. WO95E ameliorates insulin resistance and glucose tolerance in mice of diet-induced obesity, with minimal TZD use-associated side effects. We found that WO95E promotes white-to-brown adipocyte conversion and energy expenditure and hence protects against diet-induced obesity. WO95E decreases the size of adipocytes and suppresses adipose tissue inflammation. WO95E also suppresses obesity-associated liver steatosis.ConclusionsWO95E improves insulin sensitivity and glucose homeostasis and promotes browning and energy expenditure by acting as a novel PPARγ phosphorylation inhibitor/partial agonist. Our findings suggest the potential of this compound or its derivative for the therapeutic treatment of insulin resistance and obesity.

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Acetate rescues defective brain-adipose metabolic network in obese Wistar rats by modulation of peroxisome proliferator-activated receptor-γ.

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