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Celastrol, a pentacyclic triterpene, has been demonstrated to exhibit multifaceted targets to attenuate various metabolic diseases associated with inflammation. However, the underlying mechanisms by which celastrol exerts its attributive properties on high fructose diet (HFrD)\u2010induced metabolic syndrome remain elusive. Herein, the present study was aimed to elucidate the mechanistic targets of celastrol co\u2010administrations upon HFrD in rats and evaluate its potential to modulate 11\u03b2\u2010HSD1 activity. Celastrol remarkably improved glucose tolerance, lipid profiles, and insulin sensitivity along with suppression of hepatic glucose production. In rat adipose tissues, celastrol attenuated nuclear factor\u2010kappa B (NF\u2010\u03baB)\u2010driven inflammation, reduced c\u2010Jun N\u2010terminal kinases (JNK) phosphorylation, and mitigated oxidative stress via upregulated genes expression involved in mitochondrial biogenesis. Furthermore, insulin signaling pathways were significantly improved through the restoration of Akt phosphorylation levels at Ser473 and Thr308 residues. Celastrol exhibited a potent, selective and specific inhibitor of intracellular 11\u03b2\u2010HSD1 towards oxidoreductase activity (IC<jats:sub>50<\/jats:sub> value\u00a0=\u00a04.3\u00a0nM) in comparison to other HSD\u2010related enzymes. Inhibition of 11\u03b2\u2010HSD1 expression in rat adipose microsomes reduced the availability of its cofactor NADPH and substrate H6PDH in couple to upregulated mRNA and protein expressions of glucocorticoid receptor. In conclusion, our results underscore the most likely conceivable mechanisms exhibited by celastrol against HFrD\u2010induced metabolic dysregulations mainly through attenuating inflammation and insulin resistance, at least via specific inhibitions on 11\u03b2\u2010HSD1 activity in adipose tissues.<\/jats:p>","DOI":"10.1002\/biof.1793","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T05:56:53Z","timestamp":1634882213000},"page":"111-134","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Celastrol attenuates high\u2010fructose diet\u2010induced inflammation and insulin resistance via inhibition of 11\u03b2\u2010hydroxysteroid dehydrogenase type 1 activity in rat adipose tissues"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8064-695X","authenticated-orcid":false,"given":"Mohamad Hafizi","family":"Abu 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