Beneficial effects of gingerenone A, a polyphenol present in ginger, on obesity and metabolic disorders

Abstract

The World Health Organization (WHO), defines both overweight and obesity as potentially hazardous conditions of abnormal or excessive fat accumulation arising from an imbalance between energy intake and energy expenditure. Several studies have shown that excessive bodily adipose tissue is associated with metabolic disorders including type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Therefore, the inhibition of adipose tissue expansion has been proposed as a promising strategy for the prevention and/or treatment of obesity. Ginger is frequently used as an ingredient in nonprescription weight-loss products. Although several pharmacological effects of ginger extract on obesity and metabolic disease have been studied, the relative potencies of the major bioactive ginger compounds (6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), 6-shogaol (6S) and gingerenone A (GA)) for the suppression of adipogenesis and lipid accumulation have not been clearly elucidated. In the present study, I first compared the effect of the gingerols, 6S and GA on adipogenesis in 3T3-L1 preadipocytes. Our findings show that GA elicits the most potent inhibitory effect on adipogenesis in 3T3-L1 preadipocytes among the five ginger compounds. GA consistently inhibited the expression of adipogenesis- and lipogenesis-related proteins in a concentration-dependent manner. I next compared the effect of the compounds on lipid accumulation in fully differentiated 3T3-L1 adipocytes. The results revealed that only GA reduces lipid accumulation in mature adipocytes, by regulating fatty acid metabolism, showing that GA inhibits not only adipogenesis in preadipocytes but also lipid accumulation in mature adipocytes. On the basis of these results, I further investigated the effect of GA on body weight gain induced by a high-fat diet (HFD). Consistent with the in vitro data, GA supplementation significantly attenuated HFD-induced obesity by reducing fat mass. Significant losses of fat mass can cause lipodystrophy, leading to ectopic lipid deposition, particularly in the liver. Thus, I chose to investigate serum and liver lipid profiles to examine the effect of GA on lipodystrophy. Circulating free fatty acids (FFAs) and hepatic triacylglycerol (TAG) content were ameliorated to some extent by treatment with GA when comparisons were made to the HFD-alone group. These results suggest that GA suppresses HFD-induced obesity by reducing adipose tissue mass, but does not affect lipodystrophy. To further investigate the mechanisms involved in the reduction of GA-induced fat mass, I evaluated fatty acid metabolism in epididymal adipose tissue (EWAT). The results showed that GA reduces the expression of lipolysis- and lipogenesis-related proteins, while increasing fatty acid oxidation- and mitochondrial biogenesis-related transcript levels via the activation of AMP-activated protein kinase (AMPK) in EWAT. Adipose tissue inflammation caused by excessively hypertrophied fat mass has been closely associated with insulin resistance. I investigated whether the anti-obesity effect of GA might be influencing adipose tissue inflammation and glucose metabolism, and found that GA effectively suppressed adipose tissue inflammation by blocking macrophage recruitment and down-regulating expression of the pro-inflammatory cytokine, tumor necrosis factor α (TNF-α). Moreover, GA increased the expression levels of adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties. Next, I examined the effect of GA on insulin resistance by conducting a hyperinsulinemic-euglycemic clamp experiment, as such effects on adipose tissue inflammation and adiponectin expression may also affect glucose metabolism. GA effectively improved glucose intolerance induced by high-fat feeding via an increase in whole-body glucose utilization. In conclusion, I observed that GA suppressed the development of obesity and adipose tissue inflammation, while improving glucose intolerance induced by HFD in mice, highlighting GAs potential for development as a therapeutic agent for the treatment of obesity and its complications.