Abstract
BackgroundObesity occurs when the body’s energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity.MethodsIn this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments.ResultsBase on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways.ConclusionsOur results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications.
Highlights
Obesity occurs when the body’s energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity
Our results indicate that as an effective BAT activator, indirubin may have a protective effect on the prevention and treatment of obesity and related diseases, which involved in the up-regulation of uncoupled protein 1 (UCP1) expression and enhancing the BAT activity and inducing browning of subcutaneous inguinal white adipose tissue (sWAT), at least in part, via activation of protein kinase A (PKA) and p38MAPK signaling pathways
Multiple drugs in the Connectivity MAP (CMAP) were identified that had a significantly correlating gene expression pattern to that of enhancing activity in BAT and sWAT signature, including rutin and myricetin (Fig. 1b). These results demonstrate the validity of the CMAP, because both rutin and myricetin can induce the UCP1expression in differentiated adipocytes, and enhance the thermogenesis of BAT and browning of sWAT in previous publications [50, 52]
Summary
Obesity occurs when the body’s energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity. Obesity occurs when the body’s energy intake constantly exceeds its energy consumption. The available drugs to treat obesity are mainly through limiting energy intake, including inhibiting intestinal lipid absorption (such as orlistat) or inhibiting appetite (such as phenylalanine) [6]. Though these medications are effective, the adverse side effects (such as steatorrhea or depression) due to long-term use limit drug adherence of patients. There is an urgent need for safer and more effective pharmacological approaches to weight loss
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
