Low-Grade Inflammation in Obesity: Beneficial Effects of Lingonberry Supplementation

Obesity is an increasing health problem worldwide. It is associated with systemic low-grade inflammation which is a preceding state for many metabolic disorders and diseases, such as type 2 diabetes, fatty liver disease and cardiovascular diseases. In addition to healthy lifestyle and weight control, diet is in important role to prevent the development of obesity-related comorbidities. Diets containing plenty of polyphenol-rich vegetables, fruits, and berries have been found to have health-promoting properties. Lingonberry (Vaccinium vitis-idaea L.) is a wild-growing forest berry in the Northern hemisphere, and it is particularly rich in certain phenolic compounds such as proanthocyanidins, anthocyanins, flavonols, and phenolic acids. Lingonberry has been shown to have anti-inflammatory and antioxidant properties. Therefore, we hypothesized that it could have effects which may retard or prevent obesity-induced inflammatory and metabolic changes.

The aim of the present study was to explore the effects of lingonberry supplementation on inflammatory and metabolic changes associated with obesity by utilizing high-fat diet-induced experimental model of obesity in mice. Additionally, possible effective constituents in lingonberry were investigated in vitro. As study materials, we used air-dried lingonberry powder, lingonberry skin extract, and twelve lingonberry phenolic compounds. A standard high-fat diet-induced obesity model in male mice was used, and additionally, murine and human macrophage cell lines. Polarization of macrophages towards anti-inflammatory (M2) or pro-inflammatory (M1) phenotype is a phenomenon critically involved in the development of obesity induced low-grade inflammation. Macrophage M1/M2 polarization can be observed as a changed production / expression of inflammatory factors, and it was applied also in the present study.

Lingonberry powder supplementation had a moderate effect on weight and visceral fat gain, and it significantly prevented the high-fat diet-induced adverse changes in blood cholesterol and glucose levels. The levels of circulating serum amyloid A (SAA), alanine aminotransferase (ALT) and leptin were significantly lower in the lingonberry-supplemented high-fat diet fed mice than in the control high-fat diet group. Lingonberry supplementation also affected the expression of several genes in the liver, analysed by NGS-based genome wide expression analysis. The expression of many genes related to lipid or glucose metabolism and inflammation was changed by the high-fat diet, and lingonberry supplementation partly prevented these changes. Lingonberry supplementation may thus protect from the development of high-fat diet-induced adverse changes involved in the pathogenesis of nonalcoholic fatty liver disease. Moreover, lingonberry skin extract had apreventive effect on high-fat diet-induced weight and visceral fat gain. The extract also attenuated high-fat diet-induced glucose intolerance and rise in fasting glucose levels.

The effects of twelve selected lingonberry phenolic compounds were investigated on murine and human macrophages. Resveratrol, kaempferol, and proanthocyanidins were found to shift macrophage polarization towards the anti-inflammatory and healing-promoting M2 phenotype. Moreover, resveratrol and kaempferol also inhibited the pro-inflammatory M1-type activation. Mechanistically, resveratrol and kaempferol enhanced the expression of PPARγ and proanthocyanidins increased the phosphorylation of STAT6 indicating complementary effects among lingonberry compounds.

The results of the present study bring new information about the beneficial effects of lingonberries on inflammatory and metabolic changes during developing obesity. Further research is needed to confirm the translation of these findings to human obesity and define sufficient dose, and to find out active lingonberry substances and their mechanisms of action. In the meanwhile, the results encourage to use lingonberries as a part of healthy diet.