Grape polyphenols attenuate inflammation and insulin resistance in human adipocytes and obese mice.

摘要

Obesity is rapidly increasing worldwide among all age groups. Insulin resistance or type 2 diabetes is one of several debilitating health problems associated with obesity. An emerging feature of obesity and type 2 diabetes is their linkage with chronic, low-grade inflammation that begins in white adipose tissue (WAT) and eventually becomes systemic. One potential dietary strategy to reduce chronic inflammation is consumption of fruits and vegetables rich in polyphenols, including grape products, which possess anti-oxidant and anti-inflammatory properties. Notably, several clinical and animal studies have shown that supplementation with grape products like grape juice, grape powder or extracts, and red wine reduced oxidative damage and inflammation. However, the suppressive effects of grape powder on adipocyte-derived inflammation and insulin resistance remains uncertain. Additionally, the bioavailability of grape polyphenols and their ability to lower inflammation and insulin resistance in vitro and in a diet-induced obese animal model are unclear.;Therefore, the specific aims of this research were to determine the extent to which 1) grape powder extract (GPE) and several of its polyphenols decrease tumor necrosis factor alpha (TNFalpha)-mediated inflammation and insulin resistance and their mechanisms of action in primary cultures of human adipocytes (Aim 1), and 2) grape powder polyphenols are absorbed and reduce markers of inflammation and insulin resistance in high fat-fed obese mice (Aim 2). In Aim 1, GPE and quercetin, an abundant polyphenol in GPE, attenuated TNFalpha-induced a) expression of inflammatory genes, b) activation of inflammatory mitogen-activated protein kinases (MAPKs) and transcription factors nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1), c) expression or abundance of two negative regulators of insulin sensitivity, and d) suppression of insulin-stimulated glucose uptake. Taken together, these data demonstrate that GPE and quercetin attenuate TNFalpha-mediated inflammation and insulin resistance in primary cultures of human adipocytes, possibly by suppressing the activation of inflammatory MAPKs and transcription factors that cause insulin resistance. In Aim 2, it was found that a) quercetin 3-O-glucoside was one of the most abundant polyphenols detected in the sera of mice gavaged with GPE, b) high fat-fed mice supplemented with quercetin-rich grape powder had improved glucose disposal rates acutely and reduced markers of inflammation in the sera and WAT chronically, and c) quercetin 3-O-glucoside reduced several markers of inflammation in primary cultures of human adipocytes. Collectively, these findings are expected to contribute critical insights for the development of dietary strategies using grape products for the control of obesity-related conditions including inflammation and insulin resistance or type 2 diabetes. However, clinical trials are needed to determine the extent to which these findings can be reproduced in humans.