Resveratrol Reverses Damaging Effects of Obesity on the Immune System in Mice

Childhood and adult obesity are both highly problematic in the world today, particular in more developed countries.  There is a lot of speculation as to what exactly is causing this rapid increase in obese people in the past few decades, with evidence pointing to multiple mechanisms and causes.  Studies have shown that obesity increases the risk of infection in mice and in humans, and has been thought to be driven by changes in the thymus, which functions to produce T-cells in the body that aid in immunity and protect against illness and infections.

When there is significant fat accumulation in the body, the thymus is slowly overtaken by the fat cells, thus

reducing the mass available to produce protective T-cells and effectively decreasing the ability of the immune system to respond to an attack.  In other words, increased fat in the body leads to lower immune response abilities and ultimately increased risk of infections.  This generally occurs naturally during the aging process, but also has been shown to occur in obesity as well.  Restricting one’s caloric intake (i.e. not eating as much crap) has been shown to reverse this decline in T-cells in the thymus, improving not only fat levels in the body, but also the ability of the immune system to respond to infections.

Resveratrol, a frequently studied polyphenol that is naturally present in grapes, wine, and certain other foods, has been shown to prevent obesity and even reverse obesity in mice.  Additionally, it has been shown that resveratrol functions to prevent increases in the size of the liver as well as preventing the increase in fatty acids in the liver for mice fed a high-fat diet, and has also been confirmed to act similarly in the human model as well.

Though it has been shown that resveratrol helps reverse the negative effects of obesity and may help prevent obesity all together, it is not yet understood if resveratrol has any effect on the thymus, specifically whether or not resveratrol helps restore function in the thymus by improving T-cell production.

The goal of the study presented today was to examine whether or not resveratrol has any effect on restoring thymic function (i.e. restoring improved immune function) in mice fed a high-fat (obesity-inducing) diet.

Methods

Mice were fed either a high-fat or low-fat diet for 10 weeks.

Mice were randomly assigned resveratrol treatments of: 0mg/kg; 200mg/kg; or 400mg/kg.

Body weight and percent body fat were measured on a weekly basis.

In the thymus, the following were measured and analyzed:  cell counts, cell viability, number of viability of T-cells, T-cell receptors, thymic architecture (i.e. what the thymus actually looks like structurally); and protein levels.

Results

• Mice on the high-fat diet were significantly heavier than mice on the low-fat diet.
  • Mice on the high-fat diet that were supplemented with resveratrol had reduced weight gain.
  • Resveratrol had no effect on weight gain in mice fed the low-fat diet.
• Mice on the high-fat diet had significantly increased percent body fat than mice on the low-fat diet.
  • Mice on the high-fat diet that were supplemented with resveratrol had percent body fat reduced (dose-dependent).
  • Resveratrol had no effect on percent body fat in mice fed the low-fat diet.

• Thymi (plural of thymus, apparently) of mice fed the high-fat diet were significantly heavier than the thymi of mice fed the low-fat diet.
  • Resveratrol reduced the weight of thymi in mice fed the high-fat diet.
  • Resveratrol had no effect on the weight of thymi in mice fed the low-fat diet.
• Total number of T-cells was significantly reduced in mice fed the high-fat diet.
  • T-cells were significantly higher in resveratrol-treated mice fed the high-fat diet compared with untreated mice fed the high-fat diet.
  • Resveratrol had no effect on T-cell numbers in mice fed the low-fat diet.
• Lipid content was significantly higher in mice fed the high-fat diet compared with the mice fed the low-fat diet.
  • Resveratrol prevented this increase in lipid content in mice fed the high-fat diet.
  • Resveratrol had no effect on lipid content in the mice fed the low-fat diet.
• The structural anatomy of thymi in mice fed the high-fat diet was abnormal compared with mice fed the low-fat diet.
  • Resveratrol treatment prevented these abnormal structural changes in the thymi of mice fed the high-fat diet.
  • There was a loss of cortical epithelial cells in the thymi of mice fed the high-fat diet.
    • Resveratrol prevented this loss of cortical epithelial cells in the thymi of mice fed the high-fat diet.
    • Resveratrol did not have an effect on cortical epithelial cells in the thymi of the mice fed the low-fat diet.
• p-AMPK, an enzyme responsible for regulating lipids, was found to be significantly reduced in the thymi of mice fed the high-fat diet.
  • Resveratrol treatment led to an increase in p-AMPK levels in mice fed the high-fat diet.
  • Resveratrol had no effect on p-AMPK levels in mice fed the low-fat diet.

Conclusions

The results of this study indicate that resveratrol has a beneficial effect on the thymi of mice fed a high-fat diet, meaning that the negative effects of obesity on the thymus appear to be reversed by resveratrol treatment.  The thymus is responsible for producing T-cells and aiding in the protection against infection in the body.  It has been shown that obesity causes increased fat deposition in the thymus, decreased T-cell production, and ultimately increased risk of infection and illness.  The results of this study show that by treating obese mice with resveratrol, T-cell levels in the thymus are improved, and immunity is assumed to be significantly improved compared with obese mice that have not been treated with resveratrol.  By treating these obese mice with resveratrol, the risk of infection associated with obesity is significantly decreased.

In terms of dosage, this study did not find a dose-dependent effect as other studies have done in the past.  In other words, regardless of whether or not the mice were given 200mg/kg or 400mg/kg, the end result was the same.  Personally, I think in order to really test for a dose-dependent effect, they may want to include other doses than simply the two.  From this study, it would appear that 200 and 400mg/kg fall in the same range of outcomes, but perhaps a higher or lower dose would yield different results?  How low can the dose go before there is no different between resveratrol treatment and no resveratrol?

Also in regards to dosage, the authors of this study mentioned that the doses used for the mice in this

study were equivalent to doses that have been shown to be effective in humans.  While these doses are much too high to supply the adequate amounts from red wine, they are doses that can be made in supplement form.

Overall, the results of this study are very interesting and could potentially have profound effects on the treatment of obesity in both children and adults.  Of course, we’ll need to see some further studies performed in the human model to corroborate these results found in the mouse, but based on similar studies and their cross-over from the mouse to the human model, I would suspect we may see similar results.

There are a lot of other implications and discussions that can come out of this particular research, though due to space, I refrain from going through them now.  If you have any questions or anything you’d like to address related to this research, please feel free to comment and I can try and elaborate further on the study results and the authors’ interpretations of these results.

Source: Gulvady, A.A., Ciolino, H.P., Cabrera, R.M., and Jolly, C.A. 2013. Resveratrol inhibits the deleterious effects of diet-induced obesity on thymic function. Journal of Nutritional Biochemistry 24: 1625-1633.