Emodin, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, regulates adipocyte function in vitro and exerts anti-diabetic effect in ob/ob mice

Abstract

Aim: Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with the ability to ameliorate metabolic disorders in diet-induced obese mice. In the present study, we investigated the effects of emodin on adipocyte function and the underlying mechanisms in vitro, and its anti-diabetic effects in ob/ob mice. Methods: 3T3-L1 adipocytes were used for in vitro studies. 11β-HSD1A activity was evaluated with a scintillation proximity assay. The adipogenesis, glucose uptake, lipolysis and adiponectin secretion were investigated in 3T3-L1 adipocytes treated with emodin in the presence of active (corticosterone) or inactive glucocorticoid (11-dehydrocorticosterone). For in vivo studies, ob/ob mice were administered emodin (25 and 50 mg·kg -1 ·d -1 , ip) for 26 d. On the last day of administration, the serum was collected and the mesenteric and perirenal fat were dissected for analyses. Results: Emodin inhibited the 11β-HSD1 activity in 3T3-L1 adipocytes in concentration-and time-dependent manners (the IC 50 values were 7.237 and 4.204 μmol/L, respectively, after 1 and 24 h treatment. In 3T3-L1 adipocytes, emodin (30 μmol/L) suppressed 11-dehydrocorticosterone-induced adipogenesis without affecting corticosterone-induced adipogenesis; emodin (3 μmol/L) reduced 11-dehydrocorticosterone-stimulated lipolysis, but had no effect on corticosterone-induced lipolysis. Moreover, emodin (3 μmol/L) partly reversed the impaired insulin-stimulated glucose uptake and adiponectin secretion induced by 11-dehydrocorticosterone but not those induced by corticosterone. In ob/ob mice, long-term emodin administration decreased 11β-HSD1 activity in mesenteric adipose tissues, lowered non-fasting and fasting blood glucose levels, and improved glucose tolerance. Conclusion: Emodin improves the inactive glucocorticoid-induced adipose tissue dysfunction by selective inhibition on 11β-HSD1 in adipocyte in vitro and improves glycemic control in ob/ob mice.

Pharmacological Evaluation of Adipose Dysfunction via 11β-Hydroxysteroid Dehydrogenase Type 1 in the Development of Diabetes in Diet-Induced Obese Mice with Cortisone Pellet Implantation

“…In addition, it has been reported that adipose ATGL expression and lipolysis are regulated by GC signals (Villena et al, 2004;Berthiaume et al, 2007;Xu et al, 2009;Campbell et al, 2011;Serr et al, 2011;Sano et al, 2012;Wang et al, 2012). As shown in these previous similar studies, we confirmed that cortisone treatment increased the ATGL mRNA level and glycerol release in 3T3-L1 adipocytes (data not shown).…”

Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics

“…Moreover, emodin displayed an inhibitory effect on the high‐level glucose‐induced phosphorylation of ERK 1/2 and p38 MAPK (Gao et al ., 2015). Wang et al demonstrated that long‐term emodin (3 µ m ) administration improved glucose tolerance and ameliorated other metabolic disorders in ob / ob mice by the inhibition of 11β‐HSD1 activity in adipose tissue (Wang et al ., ). Emodin has been reported to exhibit protective effects against diabetic cardiomyopathy by regulating the AKT/GSK‐3β signalling pathway (Wu et al ., ).…”

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

“…Preclinical proof of concept for their efficacy in metabolic disease has been obtained in vitro and in vivo. Notably, inhibition of 11βHSD1 in 3T3-L adipocytes inhibits lipolysis and adipogenesis induced by treatment with 11-dehydrocorticosterone (the substrate for 11βHSD1 in rodents, forming active corticosterone), implying that 11βHSD1 inhibition may play an important role in regulating adipose tissue metabolism [80]. In obese, insulin resistant, rodents (e.g.…”