Regulation of adipose development and lipid metabolism by natural stilbenoid, piceatannol and resveratrol
Obesity is an increasing health threat in modern society. Obesity is a contributing factor for the development of a number of chronic diseases including cardiovascular disease, type 2 diabetes, and cancer. There has been a growing demand for discovering a strategy to prevent and combat obesity. Uncontrolled expansion of white adipose tissue via an increase in the number and size of adipocytes results in obesity. Adipogenesis which is the process of new adipocyte generation from preadipocytes contributes to an increase in the number of adipocytes. Therefore, regulation of adipogenesis is regarded as an useful strategy to target obesity. Piceatannol and resveratrol are naturally occurring stilbene compounds that are found in various fruits and plants. Piceatannol is an analogue and metabolite of resveratrol. Despite a well-documented function of resveratrol in obesity regulation, the effect of piceatannol on the development and function of adipose tissue has not yet been reported. Here we show that piceatannol inhibits adipogenesis of 3T3-L1 preadipocytes by mainly targeting the early phase of adipogenesis. Piceatannol suppressed the activation of the insulin-signaling pathway in the initial stage of adipogenesis by targeting insulin receptor (IR) and phosphatidylinositol 3-kinase. We further demonstrated that piceatannol directly interacts with IR thereby inhibiting IR kinase activity, which is likely how piceatannol inhibits adipogenesis. Resveratrol has been reported as a potential anti-obesity compound which functions in part through inhibition of adipogenesis. However, the direct target and underlying mechanism that contributes to its anti-adipogenic action remains unclear. Here we demonstrated that the anti-adipogenic action of resveratrol is largely attributable to the inhibition of the early phase of adipogenesis. Resveratrol, similar to piceatannol, inhibited the insulin signaling pathway in the early phase of adipogenesis. We revealed an inhibitory effect of resveratrol on IR activity, and a direct interaction between resveratrol and IR. Our results suggest SIRT1 activation by resveratrol plays little role in the regulation of early phase of adipogenesis. Dysregulated lipid metabolism is one of the key features of obesity. High level of adipose lipolysis and consequently, high free fatty acid influx in circulation is implicated in obesity, and contributes to associated diseases including type 2 diabetes. Here we report that piceatannol modulates lipid metabolism of adipocytes by regulating lipolysis. Piceatannol suppresses basal and stimulated adipose lipolysis with decreased protein level of the main triacylglycerol lipase, adipose triglyceride lipase (ATGL). Our results further indicated that autophagy stimulation is a main mechanism in the regulation of ATGL protein level by piceatannol. Taken together, the study herein reveals an anti-adipogenic function of piceatannol and resveratrol, and underscores IR and its downstream signaling as novel targets for piceatannol and resveratrol in the early phase of adipogenesis. Furthermore, this dissertation signifies the novel regulatory function of piceatannol on adipocytes lipid metabolism via modulation of lipolysis. The outcome of the current study provides scientific basis for prospective application of piceatannol and resveratrol on obesity prevention and dyslipidemia, as well as a novel therapeutic or preventive strategy for obesity and associated diseases.
Kim, Purdue University.
Off-Campus Purdue Users:
To access this dissertation, please log in to our