Chrysophanol, a primary active ingredient of Cassia mimosoides Linn or Rhei radix et rhizoma, has various pharmacological properties, including anticancer, antidiabetic, and anti-inflammatory, as well as blood lipid regulation. However, whether chrysophanol can mitigate obesity, and its underlying mechanisms remains unclear. This study investigated whether chrysophanol effects energy metabolism in high-fat diet- (HFD-) induced obese mice and fat-specific Sirtuin 6- (SIRT6-) knockout (FKO) mice, targeting the SIRT6/AMPK signaling pathway in brown and white fat tissue. Our results showed that chrysophanol can effectively inhibit lipid accumulation in vitro and reduce mice’s body weight, improve insulin sensitivity and reduced fat content of mice, and induce energy consumption in HFD-induced obese mice by activating the SIRT6/AMPK pathway. However, a treatment with OSS-128167, an SIRT6 inhibitor, or si-SIRT6, SIRT6 target specific small interfering RNA, in vitro blocked chrysophanol inhibition of lipid accumulation. Similar results were obtained when blocking the AMPK pathway. Moreover, in the HFD-induced obese model with SIRT6 FKO mice, histological analysis and genetic test results showed that chrysophanol treatment did not reduce lipid droplets and upregulated the uncoupling protein 1 (UCP1) expression. Rather, it upregulated the expression of thermogenic genes and activated white fat breakdown by inducing phosphorylation of adenosine 5-monophosphate- (AMP-) activated protein kinase (AMPK), both in vitro and in vivo. OSS-128167 or si-SIRT6 blocked chrysophanol’s upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) and Ucp1 expression. In conclusion, this study demonstrated that chrysophanol can activate brown fat through the SIRT6/AMPK pathway and increase energy consumption, insulin sensitivity, and heat production, thereby alleviating obesity and metabolic disorders.

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent health issues. The improvement of NAFLD is related to the activation of the farnesoid X receptor (FXR). Typhaneoside (TYP) is the main component of Typha orientalis Presl, which plays a positive role in the resistance of glucose and lipid metabolism disorders. This study aims to investigate the alleviative effect and the underlying mechanism of TYP on OAPA-induced cells and high-fat-diet (HFD)-induced mice with disorders of glucose and lipid metabolism, inflammation, oxidative stress and lower thermogenesis through FXR signaling. All the serum lipid, body weight, oxidative stress and inflammatory levels of WT mice were significantly increased after HFD administration. These mice were presented with pathological injury, liver tissue attenuation, energy expenditure, insulin resistance, and impaired glucose tolerance. These above-mentioned changes in HFD-induced mice were remarkably reversed by TYP, which improved HFD-induced energy expenditure, oxidative stress, inflammation, insulin resistance, and lipid accumulation in a dose-dependent manner by activating the expression of FXR. Furthermore, using a high throughput drug screening strategy based on fluorescent reporter genes, we found that TYP functions as a natural agonist of FXR.TYP-mediated FXR activation also significantly repressed TG hyperaccumulation in mouse primary Hepatocytes (MPHs). However, these beneficial effects of TYP were not observed in FXR^-/- MPHs. Overall, activation of the FXR pathway by TYP is related to the improvement of metabolic parameters, such as blood glucose, lipid accumulation, insulin resistance, inflammation, oxidative stress and energy expenditure in vitro and in vivo.

Pachymic acid (Pac), a major bioactive constituent of Poria cocos, is an antioxidant that inhibits triglyceride (TG) accumulation. To the best of our knowledge, the present study investigated for the first time whether Pac activated sirtuin 6 (SIRT6) signaling to alleviate oleic acid (OA)‑palmitic acid (PA)‑induced lipid metabolism disorders in mouse primary hepatocytes (MPHs). In the present study, MPHs challenged with Pac were used to test the effects of Pac on intracellular lipid metabolism. Molecular docking studies were performed to explore the potential targets of Pac in defending against lipid deposition. MPHs isolated from liver‑specific SIRT6‑deficient mice were subjected to OA + PA incubation and treated with Pac to determine the function and detailed mechanism. It was revealed that Pac activated SIRT6 by increasing its expression and deacetylase activity. Pa prevented OA + PA‑induced lipid deposition in MPHs in a dose‑dependent manner. Pac (50 µM) administration significantly reduced TG accumulation and increased fatty acid oxidation rate in OA + PA‑incubated MPHs. Meanwhile, as per the results of molecular docking and relative mRNA levels, Pac activated SIRT6 and increased SIRT6 deacetylation levels. Furthermore, SIRT6 deletions in MPHs abolished the protective effects of Pac against OA + PA‑induced hepatocyte lipid metabolism disorders. The present study demonstrated that Pac alleviates OA + PA‑induced hepatocyte lipid metabolism disorders by activating SIRT6 signaling. Overall, SIRT6 signaling increases oxidative stress burden and promotes hepatocyte lipolysis.