| Summary: | Abdulrasheed O Abdulrahman,1 Abudukadeer Kuerban,1 Zuhair Ahmed Alshehri,1 Wesam H Abdulaal,1 Jalaluddin Awlia Khan,1 Mohammad Imran Khan1,2 1Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; 2Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaCorrespondence: Mohammad Imran KhanDepartment of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaTel +966-12-6952000Email mikhan@kau.edu.saBackground: Urolithins are gut microbiota-derived polyphenol metabolites, produced following the consumption of pomegranate, berries, and nuts. Recent studies have shown the potentials of these metabolites on reducing triglycerides accumulation in cultured hepatocytes and adipocytes. In this study, we investigated the ability of both urolithin A (Uro-A) and urolithin B (Uro-B) to attenuate obesity and associated symptoms in a high-fat diet-induced obesity model in rats.Methods: Twenty-four male Wistar rats were randomly assigned to four groups. Group 1 was fed on a normal diet while groups 2, 3, and 4 were fed on a high-fat diet for 10 weeks. After this, groups 3 and 4 were treated with 2.5mg/kg body weight of Uro-A and Uro-B intraperitoneally, respectively. Body weight, serum lipid profile, hepatic antioxidant activity, hepatic lipid accumulation, fecal lipid content, and the expressions of genes involved in lipogenesis and hepatic ER stress were quantified.Results: Indeed, a high-fat diet resulted in increased body weight, visceral adipose tissue mass, and oxidative stress in rats. However, treatment with both Uro-A and Uro-B decreased body weight and visceral adipose tissue mass. These metabolites restored hepatic antioxidant capacity and decreased lipid accumulation in addition to an increase in fecal fat excretion. Moreover, both Uro-A and Uro-B treatment downregulated the expression of LXRα and SREBP1c; involved in de novo lipogenesis while upregulating PPARα expression for increased fatty acid oxidation. Furthermore, Uro-A and Uro-B decreased the expression of PERK and IRE1α; which are involved in hepatic ER stress. Taken together, our results showed the potentials of Uro-A and Uro-B in mitigating obesity symptoms and they could thus provide promising roles in the future as functional anti-obesity candidates.Keywords: de novo lipogenesis, ER stress, high-fat diet, obesity, pomegranate, urolithins
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