By Stephen DANIELLS Nutra Ingredients USA
Thirty days of supplementation with resveratrol were associated with a reduction in the size of fat cells, with genetic tests showing various pathways for fat breakdown, researchers from the Netherlands report.
A daily 150 milligram dose of resveratrol (resVida, DSM Nutritional Products) for 30 days was also associated with a decrease in the number of large and very-large fat cells (adipocytes), and an increase in small adipocytes, according to findings published in the International Journal of Obesity .
“Resveratrol supplementation for 30 days induced a shift toward an increased proportion of small adipocytes. This phenotype was accompanied by a gene expression profile indicative of increased adipogenesis, an alternative pathway of lipid breakdown by autophagy and an increased immune and inflammatory response,” wrote researchers from Maastricht University Medical Center, the Top Institute Food and Nutrition (TIFN), and Wageningen University.
“Further research is necessary to investigate whether resveratrol improves adipose tissue function.”
Resveratrol, a powerful polyphenol and anti-fungal chemical, is often touted as the bioactive compound in grapes and red wine, and has particularly been associated with the so-called 'French Paradox'. The phrase, coined in 1992 by Dr Serge Renaud from Bordeaux University, describes the low incidence of heart disease and obesity among the French, despite their relatively high-fat diet and levels of wine consumption.
Interest in the compound exploded in 2003 when research from David Sinclair and his team from Harvard reported that resveratrol was able to increase the lifespan of yeast cells. The research, published in Nature, was greeted with international media fanfare and ignited flames of hope for an anti-ageing pill.
According to Sinclair’s findings, resveratrol could activate a gene called sirtuin1 (Sirt1 – the yeast equivalent was Sir2), which is also activated during calorie restriction in various species, including monkeys.
Other studies with only resveratrol have reported anti-cancer effects, anti-inflammatory effects, cardiovascular benefits, anti-diabetes potential, energy endurance enhancement, and protection against Alzheimer’s.
While previous studies have reported potential insulin-sensitivity improvements, as well as metabolic benefits from resveratrol supplementation, the current study is said to be the first to show an effect on adipose tissue gene expression profiles.
“This is in contrast with two recent human trials, which did not show any effects on adipose tissue metabolism or gene expression after resveratrol supplementation,” wrote the researchers. “The reason for this discrepancy may possibly lie in the administered dose, which was very high in the study of Poulsen et al. (1500mg per day) [Diabetes 2013, Vol. 62, pp. 1186–1195] as compared with our study or the healthier metabolic status of the subjects in the study of Yoshino et al. [Cell Metab 2012, Vol. 16, pp. 658–664]”
The new study involved 11 obese but otherwise healthy men. The men were randomly assigned to consume 150 mg per day of a resveratrol supplement or placebo for 30 days. After this period, they went through a four week washout period before crossing over to the other group for a further 30 days.
Results showed that resveratrol was associated with significant reductions in the size of fat cells (adipocyte), “with a shift toward a reduction in the proportion of large and very-large adipocytes and an increase in small adipocytes”.
In addition, microarray analysis of genes also revealed that a downregulation of specific pathways that are linked to the formation of adipocytes from preadipocytes (precursor fat cells).
Other pathways were found to be affected by resveratrol, including the lysosomal/phagosomal pathway which relate to a of lipid breakdown by autophagy (cell degradation).
“Together, these data suggest that the reduced mean adipocyte size may underlie the previously reported improved insulin sensitivity in these subjects, as a reduced adipocyte size in combination with an improved adipogenesis may be related to an improved insulin sensitivity in humans,” wrote the researchers.
“This result, if sustained over time, may mediate a reduction in the downstream pathologies associated with prolonged obesity in humans”
Commenting independently on the study’s findings, Dr James Betz, managing director of Biotivia, told NutraIngredients-USA that the trial appears to elucidate a dose specific, versus dose dependent, array of gene expression and transduction properties of Trans-resvertrol, at least in the presence of hypertrophic liopcytes.
“It may also suggest active cross talk between macrophage initiated cytokine response and resveratrol mediated gene expression and protein modulation within the adipocytes. The immune system appears to recognize abnormally large adipocytes as zenotoxic pathogens.
“This may explain the increase in cytokine mediated cellular inflammation seen in this study, which seems to conflict with the anti-inflammatory property generally attributed to resveratrol, and observed in most other investigations.
“Also, in the majority of in vitro studies Resveratrol has been shown to be a potent inhibitor of Nf Kappa beta, a pro-proliferative enzyme. However in the present study the protein is up regulated, resulting in increased adipogenesis. These effects, as the author notes, may be localized rather than systemic.
“Concurrently, the clearance or removal of hypertrophic adipocytes appears to be up regulated via lysomal enzymatic activation and enhanced autophagy. The combined result is a higher proportion of normal healthy fat cells and a reduction of enlarged functionally compromised adipocytes. This result, if sustained over time, may mediate a reduction in the downstream pathologies associated with prolonged obesity in humans.
“The relatively moderate dosage administered chronically versus acutely administered larger doses used in some other studies may account for the difference in gene expression and transduction observed in this study.
“Consequently, it may be more useful to view dosage from the perspective of a "specific effects" correlation rather than as being simply dose dependent. Lower to moderate doses may modulate different proteonomic and biokinetic processes than higher doses.
“This might suggest that designers of theraputic applications for resveratrol would do well to consider the optimum finite dosage, rather than look for a threshhold or minimum dosage, to achieve more efficacious activation or inhibition of the target mechanism or protein,” added Dr Betz.
Source: International Journal of Obesity
Published online ahead of print, doi: 10.1038/ijo.2013.155
“The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men”
Authors: E Konings, S Timmers, et al.