Chrysophanol Alleviates Metabolic Syndrome by Activating the SIRT6/AMPK Signaling Pathway in Brown Adipocytes

Abstract

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.

The Effects and Safety of Chinese Herbal Medicine on Blood Lipid Profiles in Placebo-Controlled Weight-Loss Trials: A Systematic Review and Meta-Analysis

“…These improvements were also observed in obese mice. Chrysophanol may alleviate obesity and attenuate triglyceride accumulation by promoting lipolysis through mediating adenosine 5-monophosphate activated protein kinase (AMPK) and hormone-sensitive lipase (HSL) pathways [ 15 , 51 ]. Taken together, these active ingredients could be major contributors to the lipid modulating effects in formulations included in our review, and their cellular mechanisms could be further elucidated in computational studies.…”

Chrysophanol Inhibits the Progression of Gastric Cancer by Activating NLRP3

“…Chrysophanol attenuates airway in ammation and remodeling through nuclear factor-kappa B signaling pathway in asthma [26] . At present, Many pre-clinical research have found that Chrysophanol inhibits the proliferation of different types of tumors by targeting various signaling pathways and is a potential drug for cancer prevention or treatment [27] . Research nding that Chrysophanol inhibits the proliferation of ovarian cancer cells by activating the MAPK signaling pathway [28] .…”

SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases

“…Ergothioneine (Egt) stimulated SIRT6 enzymatic activity and restricted NF-κB signaling, reducing ROS levels and inhibiting inflammation and senescence [ 209 ]. Chrysophanol has been shown to upregulate SIRT6 expression, alleviating metabolic syndromes mediated through the SIRT6/AMPK signaling pathway [ 210 ].…”