Inflammation

Obesity is known to be accompanied by an inflammatory response (Fig. 1) in various tissues. Adipose tissue is being implicated, more and more, as a key regulator of inflammation through secretion of pro-inflammatory cytokines (i.e. TNF-α) which seem to play a chief role in affecting both endothelial function and glucose metabolism⁽Reference Avogaro and de Kreutzenberg^1, Reference Yudkin²⁰⁾. The negative influence on endothelial physiology may lead to the formation of atherosclerotic plaques⁽Reference Avogaro and de Kreutzenberg¹⁾. Endothelial dysfunction and dysfunctional glucose metabolism (ultimately insulin resistance) seem to head the two main cascades which link obesity to CVD. In fact, growing evidence is pointing to a causative relationship between inflammation and insulin resistance, as TNF-α has been established to mediate insulin resistance as a result of obesity in a multitude of rodent obesity models⁽Reference Avogaro and de Kreutzenberg^1, Reference Hotamisligil²¹⁾.

Resveratrol inhibits monocyte chemo-attractant protein secretion and gene transcription via down-regulation of TNF-induced transcription. It also reverses secretion and expression of atherogenic adipokines, actually reducing the size, density and mean area of atherosclerotic plaques, as well as the thickness of the vessel intima layer of atherosclerotic lesions⁽Reference Naderali^5, Reference Penumathsa, Koneru and Samuel²²⁾. Treatment with resveratrol, in addition to relieving glycerol-induced renal injury by suppressing the inflammatory process and by inhibiting lipid peroxidation⁽Reference Naderali^5, Reference De Jesus Soares, Volpini and Francescato²³⁾, also significantly attenuates renal dysfunction and oxidative stress in diabetic rats⁽Reference Naderali^5, Reference Sharma, Anjaneyulu and Kulkarni²⁴⁾; therefore, assuming a significant anti-inflammatory role (Fig. 2) for resveratrol is plausible⁽Reference Naderali⁵⁾.

Fig. 2 Schematic diagram of benefits of resveratrol in prominent co-morbidities of obesity.

However, evidence has arisen showing an increase in both lipid peroxidation and DNA and protein carbonyl damage markers with resveratrol treatment in the kidneys, suggesting the possibility of kidney toxicity of resveratrol and its metabolites. Resveratrol forms extensive conjugated metabolites including glucuronides, sulfates and methylated products⁽Reference Meng, Maliakal and Lu^25–Reference Wong, Gruber and Jenner²⁷⁾. Pharmacokinetic studies on acute resveratrol doses indicate significant distribution thereof to the kidneys⁽Reference Wong, Gruber and Jenner^27, Reference Bertelli, Bertelli and Gozzini²⁸⁾, with rapid excretion in urine⁽Reference Meng, Maliakal and Lu^25, Reference Wong, Gruber and Jenner^27, Reference Walle, Hsieh and DeLegge²⁹⁾. These metabolites are capable of crossing glomerular membranes and accumulating in the kidney tubules where they may act as pro-oxidants or activate oxidative stress, as seen for various polyphenolic conjugates⁽Reference Wong, Gruber and Jenner^27, Reference Monks and Lau³⁰⁾. Wong et al. ⁽Reference Wong, Gruber and Jenner²⁷⁾ hypothesised that this may have led to the increase in lipid and protein damage observed in the kidneys of the resveratrol-treated mice in the study which they undertook. However, further in vivo studies on the biological activity of resveratrol metabolites are needed to investigate the chronic effects of low-dose resveratrol on the kidney.

Given the growing popularity of resveratrol as a supplement, the possibility of kidney damage is a cause for concern and warrants further investigation, especially before the supplement is recommended for usage in obesity treatment.

Reduced endothelial function

Vascular endothelial cells maintain cardiovascular homeostasis. Importantly, in addition to the physical barrier which they create, endothelial cells secrete a number of mediators that regulate platelet aggregation, coagulation, fibrinolysis and vessel tone⁽Reference Avogaro and de Kreutzenberg¹⁾. There is strong evidence indicating an interaction between endothelium and the secretory proteins of adipocytes (adipokines), suggesting that the ability of adipokines to directly affect vascular homeostasis may be of importance in the developmental mechanism of CVD (Fig. 1) in obese patients⁽Reference Avogaro and de Kreutzenberg^1, Reference Caballero³¹⁾.

Endothelium is a contributor to the regulation of blood pressure and flow, by releasing NO as well as other compounds which contribute to both vasodilation and vasoconstriction⁽Reference Avogaro and de Kreutzenberg¹⁾. NO is the major contributor to endothelium-dependent relaxation in conduit arteries⁽Reference Avogaro and de Kreutzenberg^1, Reference Hwa, Ghibaudi and Williams³²⁾. Obesity has been shown to increase endothelium-dependent vasoconstriction in the absence of endothelial NO⁽Reference Naderali^5, Reference Steinberg, Chacker and Leaming³³⁾.

It is the increased oxidative stress in accumulated fat which plays a major role in the induction of endothelial dysfunction. Endothelium thus loses its physiological properties which include the tendency to promote vasodilation, fibrinolysis, and its anti-aggregation properties⁽Reference Avogaro and de Kreutzenberg¹⁾. NO has numerous important effects on the vasculature; these include the maintenance of basal tone by relaxing smooth muscle cells, inhibition of platelet adhesion, activation, secretion and aggregation, as well as the promotion of platelet disaggregation⁽Reference Avogaro and de Kreutzenberg^1, Reference Anderson³⁴⁾. Additionally, NO is a potent inhibitor of mechanisms ultimately leading to neointimal proliferation and atherosclerosis, through preventing endothelial leucocyte adhesion and smooth muscle cell migration and proliferation⁽Reference Avogaro and de Kreutzenberg¹⁾.

Resveratrol has the ability to increase NO synthesis, which in turn functions as an in vivo antioxidant in the ischaemic–reperfused heart, brain or kidney, and lowers oxidative stress⁽Reference Das and Maulik^8, Reference Hattori, Otani and Maulik³⁵⁾.

Cardiovascular effects

Resveratrol's protective mechanism (Fig. 2) includes its role as an intracellular antioxidant, anti-inflammatory agent, its ability to induce NO synthase (NOS) expression, as well as its ability to induce angiogenesis⁽Reference Das and Maulik^8, Reference Bhat, Kosmeder and Pezzuto¹²⁾. NO was thus identified to have a direct role in vasorelaxation when increased NOS activity was found in cultured pulmonary artery endothelial cells treated with resveratrol⁽Reference Klinge, Risinger and Watts³⁶⁾, suggesting cardioprotection by resveratrol through affecting the expression of NOS⁽Reference Das and Maulik⁸⁾.

Much evidence suggests that resveratrol-mediated cardioprotection is achieved by preconditioning⁽Reference Das and Maulik^8, Reference Hattori, Otani and Maulik³⁵⁾. Preconditioning cardioprotection is achieved by subjecting the heart to a therapeutic amount of stress, so as to disturb normal cardiovascular homeostasis and re-establish a modified homeostatic condition with increased cardiac defences that can withstand subsequent stress insult⁽Reference Das and Maulik⁸⁾. Resveratrol's pharmacological action for preconditioning of the heart takes place in an NO-dependent manner. The anti-inflammatory action itself of resveratrol seems to take place through an NO-dependent mechanism⁽Reference Das and Maulik⁸⁾.

Use of resveratrol improves post-ischaemic cardiac function regardless of the presence of glucose intake, and reduces the incidence of ventricular fibrillation and infarct size. Moreover, resveratrol increases GLUT-4 expression while reducing endothelin expression and cardiac apoptosis in ischaemic–reperfused hearts, also regardless of the absence of glucose intake, suggesting a direct protective effect on the heart⁽Reference Naderali^5, Reference Das and Maulik^8, Reference Sato, Maulik and Bagchi^37, Reference Lekli, Szabo and Juhaz³⁸⁾. GLUT-4 translocation is not involved in resveratrol's action, but the mechanism of action appears to lead to stimulation of the intrinsic activity of the GLUT-4 glucose transporters themselves⁽Reference Breen, Sanli and Giacca⁷⁾.

Insulin resistance

Insulin resistance (Fig. 1) is one of the pathophysiological mechanisms leading to diabetes mellitus⁽Reference Palsamy and Subramanian^10, Reference McCarthy and Hattersley³⁹⁾ and the state of resistance is attained through a decreased sensitivity or responsiveness of peripheral tissues to the metabolic action of insulin. This, together with the other components of the metabolic syndrome, is associated with altered endothelial function, which ultimately leads to CVD⁽Reference Avogaro and de Kreutzenberg¹⁾. Insulin resistance occurs due to high glucose levels, and can contribute to reactive oxygen species production⁽Reference Avogaro and de Kreutzenberg^1, Reference Inoguchi, Li and Umeda⁴⁰⁾ (oxidative stress then plays a role in endothelial dysfunction). The insulin-resistant state is additionally characterised by an increase in pro-inflammatory cytokines such as TNF-α, which may also contribute to hepatocellular injury⁽Reference Palsamy and Subramanian^10, Reference Grove, Daly and Bassendine⁴¹⁾. The process leading to insulin resistance leads to long-term damage, dysfunction, and failure of various organs particularly the eyes, kidneys, nerves, heart and blood vessels⁽Reference Palsamy and Subramanian^10, Reference Schuster and Duvuuri⁴²⁾.

Resveratrol is capable of scavenging some intracellular reactive oxygen species⁽Reference Bhat, Kosmeder and Pezzuto¹²⁾. Oral treatment with resveratrol significantly decreases the levels of glycosylated Hb (blood glucose indicator), suggesting that it may in fact prevent oxidative damage caused by the glycation reaction in diabetic conditions. Thus, resveratrol seems to be beneficial in preventing the pathogenesis of diabetic complications caused by impaired glucose metabolism⁽Reference Palsamy and Subramanian¹⁰⁾. Impaired glucose tolerance serves as a marker for insulin-resistant states and predicts vascular complications⁽Reference Palsamy and Subramanian^10, Reference Tominaga, Eguchi and Manaka⁴³⁾. With resveratrol treatment, the impaired glucose tolerance observed in various groups of diabetic animals was corrected to near normal, strengthening the data on resveratrol's insulin-stimulatory (Fig. 2) effects⁽Reference Breen, Sanli and Giacca^7, Reference Palsamy and Subramanian¹⁰⁾.

Data from a study by Breen et al. ⁽Reference Breen, Sanli and Giacca⁷⁾ indicate that resveratrol increases glucose uptake without stimulating the translocation of glucose transporters (i.e. GLUT-4) in skeletal muscle tissue. They demonstrated that resveratrol stimulates glucose uptake in skeletal muscle cells in a dose- and time-dependent fashion, independent of insulin.

Energy restriction

The purpose of energy restriction is to retard several aspects of ageing; these include age-related mortality, tumorigenesis, as well as physiological decline and the establishment of age-related transcriptional profiles⁽Reference Lee, Klopp and Weindruch^44, Reference Barger, Kayo and Vann⁴⁵⁾. It is proposed that energy restriction confers health benefits by provoking an organismal defence response through mild stress⁽Reference Anderson, Bitterman and Wood^46, Reference Howitz, Bitterman and Cohen⁴⁷⁾.

Animal studies have reported effects of energy restriction (Fig. 2) for resveratrol⁽Reference Baur, Pearson and Price^2, Reference Naderali^5, Reference Lekli, Szabo and Juhaz^38, Reference Barger, Kayo and Vann⁴⁵⁾, ultimately resulting in weight reduction, through prevention of abdominal obesity and TAG accumulation in hepatic cells, and improvement of lifespan of animals fed a high-energy diet. This weight-reduction effect of resveratrol is speculated to be in part attributed to its effects on adipocytes⁽Reference Baur, Pearson and Price^2, Reference Naderali^5, Reference Lekli, Szabo and Juhaz³⁸⁾. Studies have reported a decrease in adipocyte size and decreased cell viability of adipocytes (both maturing and mature) through increasing apoptosis in these cells⁽Reference Naderali⁵⁾.

Resveratrol mimics the effects of energy restriction to prevent cardiac ageing at both the transcriptional and functional levels. Additionally, mice on an energy-restricted diet or supplemented with resveratrol have improved insulin sensitivity (Fig. 2), as both these lower blood glucose levels without lowering plasma insulin⁽Reference Barger, Kayo and Vann⁴⁵⁾.

There is also a suggested up-regulation of gene expression regulating mitochondrial activity (Fig. 2) through resveratrol treatment as well as a proven increase in aerobic capacity. The increases in mitochondrial oxidative phosphorylation and aerobic capacity are associated with increased longevity, therefore improving animal survival time⁽Reference Naderali^5, Reference Dasgupta and Milbrandt⁴⁸⁾.

Mitochondria are the principal energy sources of the cell that convert nutrients into energy through cellular respiration⁽Reference Wallace^49, Reference Lagouge, Argman and Gerhart-Hines⁵⁰⁾. Compromised mitochondrial function has been linked to numerous diseases, including those of the metabolic and cardiovascular systems⁽Reference Lagouge, Argman and Gerhart-Hines^50, Reference Petersen, Befroy and Dufour⁵¹⁾. With impaired mitochondrial function, fatty acids are directed toward storage as opposed to oxidation. This may contribute to the lipid accumulation within muscle cells, which has been linked to insulin resistance in obesity and type 2 diabetes mellitus⁽Reference Lagouge, Argman and Gerhart-Hines^50, Reference Virkamaki, Korsheninnikova and Seppala-Lindroos^52–Reference Petersen, Dufour and Befroy⁵⁴⁾. In line with this, resveratrol significantly improves both muscle oxidative capacity and sensitivity to insulin in high-energy-fed mice⁽Reference Lagouge, Argman and Gerhart-Hines⁵⁰⁾.

Baur et al. ⁽Reference Baur, Pearson and Price²⁾ hypothesised that resveratrol might shift the physiology of middle-aged mice on a high-energy diet towards that of mice on a standard diet and provide the associated health benefits of such a diet without having to reduce energy intake. After 6 months of treatment, they reported that there was a clear trend towards increased survival and insulin sensitivity. Also, it was found that resveratrol-treated mice on a high-energy diet displayed decreased organ pathology (liver, pancreas) when compared with untreated mice on a high-energy diet. The ability of resveratrol to improve motor function was also noted, indicating that the effects of resveratrol are not confined to the liver. Improvements in the morphology of the aortic elastic lamina were also apparent in resveratrol-treated mice. The livers of resveratrol-treated animals showed a considerable increase in the number of mitochondria when compared with untreated high-energy-fed mice, and were not significantly different from mice on a standard diet. The data collected by this group demonstrate quite clearly that resveratrol can alleviate the negative impact of a high-energy diet on the overall health and lifespan of middle-aged mice.

The findings of this group⁽Reference Baur, Pearson and Price²⁾ showed that resveratrol does indeed shift the physiology of mice consuming high-energy diets towards that of mice on a standard diet. Resveratrol was also shown to modulate known longevity pathways and improve general health, including survival, motor function, insulin sensitivity, organ pathology, and mitochondrial number. These changes occurred, notably, without significant reduction in body weight.

It is, however, important to note that all experimental treatments have thus far been administered to middle-aged animal models; therefore, it has not yet been ascertained what the effects of resveratrol treatment would be on young animals. Although the present review focuses on the general effects of resveratrol on obesity, it cannot be ignored that children may prove to be more prone than adults to its potentially harmful effects. Thus, before any recommendation is made for the use of resveratrol in the treatment or prevention of obesity, studies will have to specifically test the product on adolescent animals, as well as compare differences in toxicity data with those of experiments performed on adult animals.