Aurantio‐obtusin improves obesity and insulin resistance induced by high‐fat diet in obese mice

Abstract

Aurantio‐obtusin (AUR) is the main bioactive compound among the anthraquinones, from Cassia seed extract. This study was conducted to identify whether AUR could improve obesity and insulin resistance, induced by a high‐fat diet in obese mice. Mice were fed a high‐fat diet for 6 weeks and were then assigned to the high‐fat diet (HFD) control group, the AUR 5 mg/kg group, or the AUR 10 mg/kg group. AUR improves glucose by activating the expression of PI3K, Akt and GLUT4, GLUT2. AUR altered the expression levels of several lipid metabolism‐related and adipokine genes. AUR decreased the mRNA expression of PPAR‐γ, FAS and increased the mRNA expression of PPAR‐α in liver. AUR lowered SREBP‐1c, FAS, SCD‐1, inflammatory cytokines, and increased the expression of PPAR‐γ, PPAR‐α, CPT‐1, and adiponectin in white adipose tissue (WAT). AUR docking with the insulin receptor showed that the residues of the insulin receptor, ectodomain, were the same as those around the emodin. The effect of AUR may be elicited by regulating the activity of the insulin signaling pathway, expression of lipid metabolism‐related genes, and expression of inflammatory cytokine markers to improve adiposity, insulin resistance, and dyslipidemia.

Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

“…Interestingly, our results also identified that the inhibition of autophagy by 3-MA completely blocked AO-induced PPARα activation ( Figure 5 ). In addition, previous studies have shown that AO increased the level of PPARγ in white tissues to improve obesity and insulin resistance ( Guo et al, 2021 ), suggesting the potential activities of AO targeting PPAR family proteins. Similarly, we found that PPAR inhibitor GW6471 markedly eliminated AO-induced decreased level of FASN and mature SREBP-1 ( Figure 5E ), indicating AO exerted its lipid-lowering function in a PPARα-related manner.…”

“…All animals were accepted 1 week of adaptive feeding before the experiment and sacrificed after 8-weeks treatment. For in vivo experiments, the doses of AO (5,10 and 15 mg/kg) were selected based on recent publications ( Xu et al, 2019 ; Guo et al, 2021 ). In chronic HFSW experiment (n = 6), mice were divided into five groups: 1) control group (chow diet); 2) NAFLD model group [HFSW, Western diet-42% Kcal from fat and 0.2% cholesterol (TD.88137, Harlan Laboratories, Inc., Indianapolis, IN, United States) plus with a high sugar solution ( d -fructose: 23.1 g/L and d -glucose: 18.9 g/L) in drinking water ( Li et al, 2021 )]; (3–5) HFSW diet with AO administration group.…”

“…Recently, increasing studies have begun to focus on the unique effects of AO on improving metabolic diseases. Under the challenge of high fat and sweet sugar, AO was found to improve adiposity and insulin resistance by downregulating the expression of lipid metabolism-related genes and suppressing inflammatory cytokines expression in white adipose tissue ( Guo et al, 2021 ). Although the above results pointed out the possibility of AO-induced hepatoprotective effects against liver steatosis, researchers temporarily focused on the anti-obesity effect of AO while paid less attention to its lipid-reducing effect and deeper mechanism involved in NAFLD.…”

Systems pharmacology dissection of the mechanisms and therapeutic potential of Cassiae semen for hepatoprotection and brightening eyes

“…2 suggested eight hub therapeutic targets of Cassiae semen as the hub targets for the treatment of hepato-related diseases, including IL6, SLC37A4, ACHE, IL2, PTGS2, PTPN1, and NOS2, linked with 16, 13, 12, 12, 12, 12, and 10 active compounds ( Table S4 ( https://www.jfda-online.com/cgi/editor.cgi?article=3417&window=additional_files&context=journal )). Interestingly, nearly half of the compounds (7 of 16 active ingredients) were experimentally confirmed to possess hepatoprotective effects via regulating IL6 expression, including chrysophanic acid [ 33 ], galangin [ 34 ], emodin [ 32 ], rhein [ 35 ], aurantio-obtusin [ 36 ], aloe emodin [ 37 ], and physcion [ 38 ]. All these findings indicated that Cassiae semen has the hepatoprotective activities through regulating multiple therapeutic targets.…”

Aurantio-obtusin exerts an anti-inflammatory effect on acute kidney injury by inhibiting NF-κB pathway

“…AO can also mitigate nonalcoholic fatty liver disease by promoting autophagy flux via inducing AMPK phosphorylation and promoting fatty acid oxidation [ 33 ]. In addition, AO alleviates obesity by regulating lipid metabolism-related genes and inflammatory cytokines [ 34 ] or by activating PPARα-dependent mitochondrial thermogenesis in brown adipose tissue [ 35 ]. Moreover, AO has the potential to treat hypertension since it can increase nitric oxide production and regulate endothelium integrity by modulating PI3K/Akt/eNOS pathway [ 23 ].…”