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Abstract

Chronic low-grade inflammation associated with cardiovascular disease and type 2 diabetes (T2D) may be ameliorated with exercise and/or diet. High levels of physical activity and/or cardiorespiratory fitness are associated with reduced risk of low-grade inflammation. Both aerobic and resistance exercise have been found to improve inflammatory status, with the majority of evidence suggesting that aerobic exercise may have broader anti-inflammatory effects. In particular, aerobic exercise appears to improve the balance between pro- and anti-inflammatory markers. Improvement in inflammatory status is most likely to occur in persons with elevated levels of pro-inflammatory markers prior to intervention. A number of dietary factors, including fiber-rich foods, whole grains, fruits (especially berries), omega-3 fatty acids, antioxidant vitamins (eg, C and E), and certain trace minerals (eg, zinc) have been documented to reduce blood concentrations of inflammatory markers. Anti-inflammatory foods may also help mitigate the pro-inflammatory postprandial state that is particularly evident after ingestion of meals high in saturated fat. Intensive lifestyle interventions involving both exercise and diet appear to be most effective. For the most part, anti-inflammatory effects of exercise and diet are independent of weight loss. Thus overweight and obese men and women, who are most likely to have a pro-inflammatory profile, do not necessarily have to normalize body mass index to improve inflammatory status and reduce risk of type 2 diabetes and cardiovascular disease.

Keywords

exercise physical activity diet cardiovascular disease

Treatments that reduce systemic inflammation may have significant value in reducing the risk of future morbidity and mortality.

Chronic diseases such as cardiovascular disease (CVD) and type 2 diabetes (T2D) are a major cause of morbidity and mortality in the United States.¹ The association between chronic inflammation and incident CVD and T2D is well established.^2-5 The pro-inflammatory state associated with these conditions results in a deleterious milieu that is characterized by vascular endothelial dysfunction and abnormalities in glucose metabolism and insulin resistance, which in turn are associated with atherosclerotic disease progression.

The inflammatory response is associated with a localized and a systemic, or acute phase, response. This response results in the production of hepatocyte-derived acute phase proteins such as C-reactive protein (CRP) and has been mimicked in experimental models by the injection of cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6).^5,6 Chronic low-grade inflammation is characterized by a 2- to 4-fold increase in the systemic concentrations of these cytokines. Measuring the levels of multiple inflammatory markers is preferred to measuring just a single marker, such as CRP, which is the most frequently assessed circulating inflammatory marker. It is important to note that both pro- and anti-inflammatory cytokines exist, and the balance between the two may influence the atherosclerotic disease process.

A significant body of evidence points to TNF-α as a significant player in the pathogenesis of insulin resistance and the metabolic syndrome.^7,8 It appears that TNF-α produced by adipose tissue is the main source of circulating TNF-α.^9-11 TNF-α has been shown to impair insulin stimulated glucose uptake in cell culture and in animal studies.^10,11 In human infusion studies, TNF-α has been found to adversely affect the insulin signaling cascade that regulates glucose transporter type 4 (GLUT4) translocation and glucose uptake.¹² Thus it appears that TNF-α represents the molecular link between low-grade systemic inflammation, insulin resistance, and the eventual appearance of atherosclerotic disease.

Although IL-6 has been observed to be pro-inflammatory in the setting of sepsis, its role in the setting of acute exercise appears to be principally anti-inflammatory.^13-15 It is also important to note that whereas resting/basal (cytokine) IL-6 is thought to be largely driven by inactivity, acute (myokine) IL-6 elevations appear to be driven by contracting skeletal muscle, and are anti-inflammatory. Interleukin-6 appears to exert anti-inflammatory effects primarily by acutely inhibiting TNF-α.¹⁶ Starkie et al¹⁶ demonstrated that acute exercise, during which IL-6 was elevated, attenuated TNF-α production following infusion of Escherichia coli lipopolysaccharide endotoxin. This attenuation of TNF-α was also observed by the infusion of recombinant human IL-6, suggesting that exercise mediates anti-inflammatory activity via increases in myokine IL-6 production.

Treatments that reduce systemic inflammation may have significant value in reducing the risk of future morbidity and mortality. Both exercise and diet have been documented to reduce pro-inflammatory markers, which likely contributes to the reduced incidence of chronic diseases associated with healthy diet and high levels of physical activity.^17,18 In this review, we briefly summarize the relevant lifestyle interventions involving exercise and/or diet that have been shown to have salutary effects on reducing markers of inflammation.

Exercise and Inflammation

Anti-inflammatory effects of exercise are well established.^20-26 Data from observational studies indicate that increased physical activity and/or cardiorespiratory fitness is associated with lower risk of elevated inflammatory markers.^22,25,27 Physical activity may also be beneficial for people with chronic inflammatory diseases.²³ Furthermore, exercise may elicit local anti-inflammatory adaptations in skeletal muscle (eg, reductions in TNF-α, IL-6, and IL-1β gene expression) that may not be evident in the systemic circulation.²⁸

Aerobic Exercise Interventions

Aerobic exercise is most effective in subjects with elevated inflammatory markers.^29,30 A number of aerobic exercise interventions, lasting 12 weeks to 6 months, have been shown to reduce circulating levels of CRP and pro-inflammatory interleukins.^31-38 With few exceptions,³⁵ most of these studies show that the exercise-induced reductions in pro-inflammatory markers are independent of weight/fat loss. In patients with CVD, 12 weeks of training 3 times per week for 45 minutes at 70% to 80% of HRmax (maximal heart rate), reduced CRP by 48%, IL-6 by 42%, and interferon-γ (IFN-γ) by 10%, and increased anti-inflammatory marker IL-10 by 42%, despite no significant changes in body weight.³⁴ The number of patients in the high-risk category (CRP > 3.0 mg/L) was reduced by 46%. Whereas none was in the low-risk category (CRP < 1.0 mg/L) before training, 11% of the patients were in the low-risk category after training. Similarly, Milani et al³⁷ reported that a 6-month cardiac rehabilitation program consisting of 3 structured exercise sessions per week, plus encouragement to exercise an additional 1 to 3 times per week on their own, reduced CRP by 41%. The reduction in CRP was the same in patients not on statin therapy (−38%) as in those patients receiving statin therapy (−42%).

Aerobic exercise training is also effective in reducing inflammatory markers in T2D.^31,33 In overweight men and women with T2D, 6 months of exercise training (4 sessions/week; 45-60 minutes; 50% to 75% Vo₂peak) reduced CRP (−40%) and IL-18 (−35%), and increased the anti-inflammatory marker IL-10 (+28%).³¹ This resulted in a 50% reduction in IL-18/IL-10 ratio. This may have important clinical consequences as inflammatory balance may contribute to CVD risk, and the IL-18/IL-10 ratio has been reported to be an independent predictor of coronary events in patients with acute coronary syndrome.³⁹ IL-6 also appears to be reduced in T2D as a result of exercise training. Dekker et al³³ reported that 12 weeks of exercise training (5 times per week; 60 minutes per session; ~60% Vo₂peak) in 8 obese adults with T2D reduced IL-6 by 52%. In this study, subjects were fed meals during the 12 weeks of training designed to prevent weight loss, which emphasizes the weight loss–independent effects of aerobic exercise training.

Much of the reduction in inflammatory markers observed after months of exercise training may actually occur relatively soon after starting an exercise program.³⁶ In sedentary middle-aged men, approximately two thirds of the reduction in IL-6 after 24 weeks of training was observed after just 4 weeks of training. This was exclusively demonstrated in the men with initially elevated levels of IL-6, as reductions in IL-6 after training were highly correlated (r = 0.90) with baseline concentration. These results suggest that individuals with high levels of baseline inflammatory markers stand to benefit the most from exercise training.

Although most aerobic exercise training studies have used continuous exercise sessions lasting 30 to 60 minutes, high-intensity aerobic interval exercise training may also be beneficial for improving inflammatory status.³⁸ In patients who underwent percutaneous coronary intervention with stent implantation, 6 months of aerobic interval exercise training (four 4-minute intervals at 80% to 90% HRmax, interspersed with 3 minutes of active recovery at 60% to 70% HRmax; 3 days per week) reduced CRP by 27%, whereas no change occurred in the control group.³⁸ The reductions in CRP were inversely correlated (r = −0.48) with improvements in endothelial function, assessed by flow-mediated dilation of the brachial artery.

Muscle contraction–induced increases in myokines may mediate some of the health effects of exercise and play a significant role in protection against chronic low-grade inflammation.⁴⁰ Much of this effect may be due to the anti-inflammatory effect of an acute bout of exercise¹⁶ (ie, perhaps analogous to acute postexericse hypotension and the postexercise lowering of plasma trigylcerides).

Resistance Exercise Interventions

Resistance exercise training has been shown to result in reductions in CRP.^41,42 In a recent review, de Salles et al⁴² found that the majority of resistance training studies that evaluated CRP reported significant reductions in this inflammatory marker, with the greatest effects observed in overweight and obese populations, who generally have higher CRP levels at baseline. The results of one recent study suggest that resistance exercise training may have more impact on African American men than Caucasian men.⁴³ Six weeks of resistance training reduced CRP levels in African American men by 52% but had no effect on CRP levels in Caucasian men. This could be because of the fact that the baseline CRP levels were much higher in the African American men (4.84 mg/L vs 1.34 mg/dL). With regard to dosage, de Salles et al⁴² suggest that training durations longer than 16 weeks, with frequencies ≥2 times/week and intensities ≥~80% of a 1 repetition maximum may be required for reductions in CRP.

The majority of randomized control trials show a significant increase in adiponectin after resistance training.⁴² In contrast, none of the studies reviewed by de Salles et al found that resistance training reduced levels of TNF-α. Similarly, IL-6 does not appear to be influenced by resistance training.⁴¹ However, the number of studies of the effects of resistance training on inflammation is less than that of aerobic exercise training, and thus conclusions at this time must be viewed in this context.

Ten weeks of resistance training in older women training was found to lower lipopolysaccharide-stimulated cytokine production in blood cultures. Following training, Toll-like receptor 4 (TLR4) levels are typically reduced to the same as those observed in subjects that have been active for several months or years.²⁰ TLRs are recognized as primary signaling molecules for lipopolysaccharides, and TLR4 signaling is known to activate innate immune responses and the inflammatory process. Higher levels of physical activity or exercise intervention result in blunted inflammation and lower monocyte TLR expression. TLR4 expression appears to be lower in physically active young and old subjects as compared with sedentary, age-matched controls.²⁰

Direct comparisons of aerobic versus resistance training are sparse,^44,45 and it is not clear if one mode of exercise training is superior. Kohut et al⁴⁵ observed significant reductions in CRP in older adults after 10 months of aerobic exercise training but not after strength training. However, Martins et al⁴⁴ reported that both aerobic and resistance training reduced CRP in older adults (51% vs 39%). Interestingly, Martins et al found that the greatest reductions in CRP were observed 16 weeks after the formal exercise programs had stopped. The reasons for the delay in the exercise training effect require clarification.

Combined Aerobic and Resistance Exercise Interventions

Not unexpectedly, combined aerobic and resistance exercise programs have been shown to improve inflammatory status.^32,46-48 In a recent report on patients with T2D and metabolic syndrome, 12 months of combined aerobic and resistance training resulted in greater reductions in circulating CRP and IL-6 than either aerobic exercise training alone.⁴⁶ Furthermore, both high-intensity exercise programs, but especially the combined aerobic and resistance training, led to reductions in TNF-α, IL-1β, and IFN-γ, and increases in IL-4, IL-10, and adiponectin, suggesting that, at least for patients with T2D and metabolic syndrome, this type of training attenuates pro-inflammatory pathways and stimulates anti-inflammatory pathways.⁴⁶ It is important to emphasize that these beneficial changes after 12 months of exercise training were independent of weight loss and occurred without any reduction in total body fat.

In both young⁴⁷ and older^47,48 sedentary men and women, combined aerobic and resistance training programs reduced some, but not all, markers of inflammation. In 70- to 89-year-old men and women, a 12-month physical activity intervention consisting of aerobic, strength, balance, and flexibility exercises, reduced circulating levels of IL-6 primarily in those with high baseline values but did not affect CRP.⁴⁸ However, in another study, 12 weeks of combined aerobic and resistance exercise training reduced CRP similarly (58%) in both young and older, initially sedentary subjects, but did not affect TNF-α, IL-6, or IL-1β.⁴⁷ The authors speculated that repeated bouts of intense exercise that accompany regular exercise training may act to downregulate CRP protein production in the liver. Indeed, it is important to distinguish between chronic low-grade inflammation and the acute inflammatory response to an acute bout of exercise^5,14 and acknowledge that exercise training itself may modify the adipokine response to acute exercise.⁴⁹

Combined aerobic and resistance training results in significant anti-inflammatory adaptations in skeletal muscle.³² In frail older men and women, 12 weeks of combined aerobic (20-30 minutes at 75% HRmax; 30-40 minutes of progressive resistance training at 65% to 80% 1 repetition maximum; 3 days per week) reduced muscle TLR4 mRNA by 37%, and decreased TNF-α and IL-6 mRNA by 50%.³² In addition, the combined exercise training doubled the content of the anabolic muscle mechanogrowth factor mRNA. Because inflammation and sarcopenia pose significant health issues for older persons, combined aerobic and resistance exercise programs may have considerable salutary effects in this population.

Dietary Factors to Treat and Prevent Inflammation

Dietary Fiber

Observational studies consistently reveal that dietary fiber is inversely correlated with markers of inflammation.^50-56 In the National Health and Nutrition Examination Survey 1999-2000, dietary fiber was inversely correlated with CRP.⁵⁰ In the Finnish Diabetes Prevention Study, dietary fiber intake predicted decreases in CRP and IL-6.⁵³ The results on fiber may explain the finding that whole grain consumption is inversely correlated with CRP.⁵⁷ Postmenopausal women who consumed ≥1 serving/day of whole grains (16 g, or ½ cup 100% whole grain) had lower probability of having moderate (1-3 mg/L) or elevated (>3 mg/L) CRP compared with women who did not consume whole grains.⁵⁷

Dietary interventions confirm the results of observational studies.⁵⁵ In a review of clinical trials, North et al⁵⁵ reported that 6 of 7 clinical trials showed 25% to 54% reductions in CRP with increased dosages of dietary fiber ranging from 3.3 to 7.8 g/MJ. Thus, a dietary fiber intake of at least 25 to 30 g/d may be necessary to reduce CRP.^53,55 Data from the British Regional Heart Study, for example, found that dietary fiber intake <20 g/d was associated with the highest levels of CRP and IL-6 and also with significantly increased risk of T2D in older men.⁵⁶ Fiber supplements may be just as effective as a high-fiber diet.⁵⁸ In a randomized crossover study, 3 weeks of either a high-fiber (30 g/d) diet (Dietary Approaches to Stop Hypertension) or a fiber (psyllium)-supplemented diet (30 g/d) reduced CRP by the same amount (~13% to 18%).⁵⁸

The mechanism for the beneficial effect of dietary fiber on reducing markers of systemic inflammation is not known. Other dietary factors associated with a high-fiber diet may contribute to the apparent fiber effect. However, dietary fiber is a significant source of butyrate in the intestine, and butyrate has a potent anti-inflammatory effect both in vivo and in vitro.⁵⁹

Berries

Fruits have abundant quantities of anti-inflammatory phytochemicals,⁵² and this is particularly true for berries. In addition to being good sources of fiber, berries are excellent sources of polyphenols, especially anthocyanins.^60-63 Roughly 400 individual anthocyanins have been identified and are most concentrated in the skins of berries.⁶⁰ Anthocyanin content is proportional to the color intensity of the berry. Data from the 1999-2002 National Health and Nutrition Examination Survey revealed an inverse association between anthocyanin intake and CRP.⁶¹ Berries counteract free radical generation and attenuate inflammatory gene expression.⁶⁰ Blueberry and cranberry anthocyanins have been shown to reduce TNF-α-induced upregulation of several inflammatory mediators, including IL-8, monocyte chemotactic protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1).⁶³ Berries may also be used to counteract postprandial metabolic and oxidative stresses associated with CVD.⁶⁰ Because of the deterioration in nutritional value associated with processing methods, consumption of fresh or frozen whole berries may be preferred to intake of juices or extracts.⁶⁰

Omega-3 (n-3) Unsaturated Fatty Acids

The n-3 long-chain polyunsaturated fatty acids in marine foods and fish oil supplements (eg, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) may specifically affect TNF-α and IL-6 production by monocytes. In a 12-week intervention, young, healthy men received doses of fish oil supplying 0.3, 1.0, and 2.0 g n-3 long-chain polyunsaturated fatty acids during weeks 0 to 4, 5 to 8, and 9 to 12, respectively.⁶⁴ All n-3 dosages inhibited TNF-α and IL-6 production by isolated mononuclear cells as compared with baseline (range of inhibition: 72% to 86%). Fish oil supplements providing 1.4 to 6.0 g n-3 polyunsaturated fatty acids have been reported to significantly reduce circulating concentrations of TNF-α, CRP, and IL-6, and increase adiponectin.⁶⁵ Some investigations, however, were unable to demonstrate anti-inflammatory effects with fish oil supplements.^66,67

The American Heart Association currently recommends fish consumption, particularly fatty fish such as salmon, tuna, and mackerel, at least 2 days per week to promote a healthy cardiovascular system in individuals without CVD.⁶⁸ This level of fatty fish consumption would equate to approximately 0.45 g DHA + EPA per day, a level of ingestion that was effective at reducing TNF-α production by isolated monocytes as discussed above.⁶⁴ In patients with established CVD, the American Heart Association recommends higher intakes of DHA + EPA, 1 to 4 g/d provided as fish oil capsules in consultation with a physician, and states that the anti-TNF-α activity of the long-chain n-3 fatty acids is a possible mechanism for the beneficial cardiovascular effects of fish oil supplementation.⁶⁸

α-Linolenic acid (ALA), a plant-derived short-chain n-3 unsaturated fatty acid, may also inhibit TNF-α production by isolated monocytes. In a randomized, crossover trial, hypercholesterolemic adults consumed 3 experimental diets for 6 weeks, including a diet rich in flaxseed oil (19.1 g ALA), and 2 control diets containing 2.3 and 10.6 g ALA, respectively.⁶⁹ Compared with the 2 control diets, the high-ALA flaxseed oil diet reduced TNF-α production by monocytes 20% to 22% and serum TNF-α concentrations 23% to 45%. In vitro work demonstrated that ALA inhibited TNF-α mRNA expression in a murine macrophage cell line.⁷⁰ Two tablespoons of flaxseed or walnuts and 2 tablespoons of flaxseed oil daily would provide the reported anti-TNF-α dosage of ALA (ie, 19 g).⁶⁹

Vitamin E

Vitamin E is a fat-soluble antioxidant that effectively stops the oxidation of polyunsaturated fatty acids in cell membranes and plasma lipoproteins. Vitamin E also functions in cell signaling and gene expression. Vegetable oils, unprocessed cereal grains, and nuts are the main dietary sources of vitamin E, and the recommended dietary allowance for vitamin E is 15 mg (or 22 IU) per day.

Daily vitamin E supplementation (800 mg or 1200 IU) significantly reduced TNF-α production in whole blood in subjects with metabolic syndrome (15% reduction after 6 weeks) or with CVD (25% reduction after 6 months),^71,72 and reduced CRP by 32%.⁷² Lower doses of vitamin E supplementation (400 mg/d) have also been reported to reduce TNF-α.⁷³ Additionally, daily vitamin E supplementation (400 mg/d) has been reported to reduce IL-1β, IL-8, and lipopolysaccharide-induced cytokine production by mononuclear cells.⁷⁴ In contrast, some investigations were unable to demonstrate anti-TNF-α effects with daily vitamin E supplementation.^75,76 Recent trials suggest that the TNF-α response to vitamin E supplementation may depend on polymorphisms at the TNF-α −308G>A gene⁷⁷ and/or on the baseline TNF-α production response.⁷⁸

These reports suggest that daily dosages of vitamin E ≥400 mg/d (or 600 IU/d) may reduce TNF-α production and inflammation. Since typical US diets generally supply less than the recommended dietary allowance (15 mg/d), vitamin E supplementation would be necessary to achieve the anti-TNF-α effects noted in these research trials. Vitamin E supplementation up to 1000 mg/d is considered safe by the US Food and Nutrition Board of the Institute of Medicine,⁷⁹ yet meta-analyses of well-designed randomized trials examining the efficacy of vitamin E supplementation suggest that high-dose vitamin E supplementation (≥268 mg/d) may increase risk of all-cause mortality.^80,81However, these meta-analyses have been questioned since many of the trials included a high proportion of male patients and patients who were already at high risk for death. Moreover, reanalyses of the original meta-analyses using different meta-analytic approaches yielded contradictory results.⁸² Also, since a small mortality benefit was noted with low doses of vitamin E (200 mg/d) in the original meta-analysis,⁸⁰ vitamin E supplementation at 200 to 250 mg/d may represent a prudent, anti-inflammatory strategy. At present, however, the American Heart Association 2011 guidelines for prevention of CVD in women strongly recommend against supplementation with vitamin E for primary or secondary prevention (class III).⁸³

Zinc

Zinc is required for many reactions critical for normal cell metabolism, including DNA synthesis, cell division, immune system function, and protein synthesis. Beef, chicken, fortified cereals, and nuts are the main dietary sources of zinc, and the recommended dietary allowance for zinc is 8 to 11 mg/d. In the United States, nearly 40% of adults 19 to 50 years old and 50% of older adults may not be consuming adequate amounts of zinc.⁸⁴

In 20 healthy adults participating in a randomized controlled trial, zinc supplementation of 45 mg/d as zinc gluconate for 8 weeks decreased the expression of genes encoding TNF-α and IL-1β by isolated monocytes, and protected mononuclear cells from TNF-α-induced nuclear factor-κ B (NF-κB) activation.⁸⁵ In a healthy, noninstitutionalized elderly population participating in a randomized controlled trial, zinc supplementation (45 mg/d as zinc gluconate for 12 months) was shown to reduce TNF-α production by isolated monocytes by 26%.⁸⁶ Moreover, zinc supplementation significantly reduced the total incidence of infections by 80% and significantly reduced markers of plasma oxidative stress as compared with the placebo treatment.

In 18 zinc-deficient patients characterized by increased blood levels of TNF-α, supplementation with 25 mg zinc acetate 3 times daily for 3 months decreased lipopolysaccharide-induced TNF-α production by isolated monocytes by 20%, and also decreased IL-1β mRNA and TNF-α-induced activation of NF-κB.⁸⁷ The downregulation of TNF-α production in these patients appeared to normalize the expression of TNF-α when production rates were compared with that of healthy, age-matched controls. Yet in a small randomized control trial in 6 healthy, young men, modest zinc supplementation (15 mg zinc as zinc sulfate) for 4 days increased TNF-α gene expression as compared with placebo.⁸⁸ However, the short duration and the small sample size of this latter trial limit data interpretation and possible relevance.

Zinc supplementation up to 40 mg/d is considered safe by the US Food and Nutrition Board of the Institute of Medicine, but chronic intakes of zinc above this level may adversely affect copper status, immune system function, and plasma concentrations of high-density lipoproteins.⁷⁹ Zinc supplementation has been demonstrated as an effective therapeutic and preventive agent for many conditions, including tuberculosis, pneumonia, acute lower respiratory tract infection, and the common cold,⁸⁹ and recent data suggest that zinc supplementation may also possess effective anti-TNF-α and anti-inflammatory roles.

Reduced Intake of Saturated Fatty Acids

Dietary fats consist of saturated fatty acids, which include the hydrogenated fatty acids, and unsaturated fatty acids. High intakes of saturated fatty acids, found primarily in red and processed meats, dairy foods, coconut and palm oils, margarines, and fried foods, have been linked with elevated concentrations of serum total and low-density lipoprotein (LDL) cholesterol and increased risk for CVD. Recent investigations indicate that saturated fat ingestion may also increase TNF-α production by monocytes and thus initiate inflammatory processes directly.

Healthy middle-aged adults with moderately elevated LDL cholesterol participating in a double-blind, crossover trial, consumed each of 3 experimental diets (high butter, high stick margarine, and high soybean oil) for 5 weeks.⁹⁰ The diet that included 20% energy from stick margarine raised TNF-α and IL-6 production by isolated blood monocytes by 58% compared with the diet rich in polyunsaturated fat (20% of energy from soybean oil).

In patients with heart failure, Lennie et al⁹¹ reported that serum TNF-α was 39% higher on a high-saturated fat diet compared with a low-saturated fat diet, and 34% higher on a diet high in hydrogenated fat versus a diet low in hydrogenated fat. Low TNF-α was associated with significantly longer event-free survival during a 24-month follow-up.⁹¹

Saturated fatty acids may enhance induction of inflammatory genes in white adipose tissue, immune cells, and myotubes.⁹² Palmitate, for example, increases expression and secretion of TNF-α, IL-6, IL-10, and TLR4.⁹² Hence, in addition to reducing serum total and LDL cholesterol, restricting saturated fats in the diet may also help to reduce risk of chronic low-level inflammation.

Postprandial Inflammation

In addition to the long-term effects of various dietary factors on low-grade systemic inflammation, acute inflammatory reactions may result from ingestion of meals. Postprandial dysmetabolism may play a significant role in the genesis of a number of chronic diseases, including atherosclerosis and T2D.⁹³ This is particularly relevant in view of the fact that we spend most of our waking hours in a postprandial state, especially after large meals containing a significant amount of fat.^94-96

Postprandial hyperglycemia and hypertriglyceridemia appear to be pro-inflammatory,^93,97 with the peak postprandial inflammatory response occurring approximately 4 hours after ingestion of the meal.⁹⁷ This postprandial pro-inflammatory response is added to the low-grade inflammation associated with obesity, poor diet, and a sedentary lifestyle. The quality of the meal, rather than the calorie content, appears to be most important. A 900-kcal high-fat, high-carbohydrate meal (51 g fat, 81 g carbohydrate, 32 g protein) produced a significant inflammatory response (increases in lipopolysaccharide concentration and expression of TLR2, TLR4, and suppressor of cytokine signaling-3 (SOCS-3) proteins, reactive oxygen species generation, and nuclear factor-κB binding activity), but a calorically equivalent American Heart Association–recommended meal rich in fiber and fruit produced no postprandial inflammatory response.⁹⁸

A single high-fat meal is associated with increased inflammatory cytokine production.⁹⁴ In healthy adults with and without T2D, plasma concentrations of TNF-α and IL-6 were elevated 2 to 4 hours following consumption a high–saturated fat meal (760 total kcal; 59% energy from total fat and 25% energy from saturated fat) but not following the consumption of a high-carbohydrate, low-fat meal (760 total kcal; 73% energy from carbohydrates).⁹⁴ Similarly, Esposito et al⁹⁹ reported that a high-fat meal increased IL-18 and decreased adiponectin in both diabetic and nondiabetic subjects, whereas a high-carbohydrate, high-fiber (16.8 g) meal decreased IL-18 in both groups. IL-18 is a potent pro-inflammatory cytokine that may play a role in plaque destabilization. These studies suggest that the pro-inflammatory effects of high-energy meals are primarily because of the high fat content of the meals.

Subsequently, other investigators have reported pro-inflammatory responses following ingestion of high-fat meals.^96,100,101 In healthy subjects, Derosa et al¹⁰⁰ demonstrated that an oral fat load (1147 kcal; 68% fat) induced a significant systemic inflammatory response characterized by elevations in TNF-α, CRP, IL-6, and soluble cell adhesion molecules sICAM-1, sVCAM-1, and sE-selectin. Esposito et al⁹⁶ showed that the rise in postprandial blood levels of TNF-α was significantly correlated with the impairment in postprandial endothelial function after a high-fat (760 kcal; 59% fat) meal in persons with metabolic syndrome. Because there was no relation between TNF-α and endothelial function at baseline, this suggests an important role for TNF-α in mediating endothelial dysfunction in the postprandial metabolic state.⁹⁶

Not all studies report a consistent pro-inflammatory response following consumption of high-fat meal.¹⁰² The amount of saturated fatty acids may be an important factor, and the ratio of n-3 polyunsaturated fatty acids (generally anti-inflammatory) to n-6 polyunsaturated fatty acids (generally pro-inflammatory) in the meal may influence the postprandial inflammatory response.⁹⁷

Dietary Strategies to Mitigate Postprandial Inflammation

A number of dietary factors may mitigate postprandial inflammation.¹⁰³ Anti-inflammatory foods (such as those already discussed above) may provide protection when ingested with pro-inflammatory foods. For example, the addition of a 300-kcal orange juice drink to a 900-kcal high-fat, high-carbohydrate meal (51 g fat, 81 g carbohydrate, 32 g protein) eliminated the postprandial increases in matrix metallopeptidase-9 (MMP-9) mRNA, TLR2 and TLR4 mRNA or protein, SOCS-3, and endotoxin, that were observed when the meal was consumed with either water or glucose.⁹⁸ The key anti-inflammatory nutrients in orange juice remain to be identified. The flavonoids naringenin and hesperidin are potent inhibitors of reactive oxygen species generation.¹⁰³ Vitamin C in orange juice may also play a role. Nappo et al⁹⁴ for example, showed that the addition of 1000 mg vitamin C and 800 IU vitamin E to a high-fat meal eliminated the postprandial increase in TNF-α, IL-6, sVCAM, and sICAM observed after the ingestion of the high-fat meal without vitamins. Fiber-rich meals may function in a similar manner.^98,104 More research is needed to determine potential for consuming anti-inflammatory foods to minimize postprandial inflammation.

Combined Exercise and Dietary Interventions to Reduce Inflammation

Comprehensive lifestyle interventions involving both exercise and diet have been shown to reduce markers of inflammation.^105-109 Two to 3 weeks of daily aerobic exercise and consumption of an ad libitum high-fiber, low-fat (10% to 15% of total energy) diet reduced a number of inflammation-associated proteins, including CRP, sICAM, soluble P-selectin, and MMP-9 in obese men with metabolic syndrome.¹⁰⁵ This same intervention also reduced the high-density lipoprotein inflammatory index from pro- to anti-inflammatory in obese men with CVD risk factors,¹⁰⁶ and reduced CRP, sICAM, and serum amyloid A in postmenopausal women with multiple risk factors for CAD.¹⁰⁷ In a study of 27 men and women with CAD, 12 weeks of 10%-fat, plant-based diet, 3 hours a week of moderate-intensity exercise, and 1 hour a day of stress management, reduced CRP by 23% and IL-6 by 51%.¹⁰⁹ A 57% decrease in TNF-α was not statistically significant, most likely because of the high standard deviation in baseline level.

Potential Mechanisms for Improved Inflammatory Status With Lifestyle Intervention

Exercise and/or Diet Effect Is Independent of Weight/Fat Loss

Obesity is associated with chronic low-grade inflammation, and markers of inflammation such as TNF-α, CRP, and IL-6 have been reported to correlate positively to adipocyte size.¹¹⁰ Additionally, subcutaneous adipose tissue removal via liposuction has been shown to reduce proinflammatory markers TNF-α, CRP, IL-6, and IL-18.¹¹¹ These studies are consistent with findings from intervention studies reporting significant reductions in inflammatory markers accompanied by loss of body fat.^{30,35,36,38,109} In fact, Church et al³⁵ found that among subjects participating in the Inflammation and Exercise (INFLAME) study, only those subjects in the highest tertile of body fat loss experienced a reduction in CRP. They concluded that exercise training without fat loss is not associated with a reduction in CRP.

In contrast, many studies show that inflammatory markers can be reduced with exercise and diet in the absence of weight/fat loss.^* Even in studies reporting reductions in both body fat and inflammatory markers, the amount of fat loss is very small,^38,54,112 and the correlations between fat loss and decreases in inflammatory markers are very small and/or not statistically significant.^33,105-107 The fat loss–independent effect of exercise training is best exemplified by Milani et al,³⁷ who studied 235 patients with coronary heart disease before and after cardiac rehabilitation. Patients who lost weight (6 pounds; 3% of initial body weight) reduced their CRP levels by 31%; patients who gained weight (6 pounds; 3% of initial body weight) reduced their CRP levels by 42%. Furthermore, Lambert et al³² reported that significant weight loss (7.5 kg) via diet had no effect on markers of muscle inflammation whereas exercise training in the absence of weight loss resulted in significant reductions in TLR4 mRNA (37%), and IL-6 and TNF-α mRNA (50%). Thus weight/fat loss itself does not appear to be the cause of the reduction in low-grade inflammation observed after lifestyle interventions involving exercise and diet.

Reduction in Adipose Tissue Hypoxia

One novel mechanism through which exercise may improve inflammatory profiles is through mediation of adipose tissue blood flow. Adipose tissue hypoxia has been found to occur in obese individuals and results in triggering of the NF-κB-inducible and hypoxia-inducible factor-1 α-mediated pathways. This has been shown to induce gene expression of TNF-α, IL-1β, IL-6, MCP-1, plasminogen activator inhibitor-1, macrophage migration inhibition factor, inducible nitric oxide synthase, and MMP-2 and MMP-9, resulting in a significant pro-inflammatory profile.¹¹³ Exercise has been shown to improve adipose tissue blood flow¹¹⁴ and may represent a potential mechanism through which exercise could result in a blunted inflammatory profile. This remains to be experimentally tested in humans.

Conclusions

In summary, treatments that reduce systemic inflammation may help reduce risk of future morbidity and mortality. At present, pharmacotherapy with rosuvastatin is indicated in asymptomatic adults with elevated CRP who are at high risk of cardiovascular events.¹¹⁵ However, reductions in CRP with statin therapy are no better than that achieved by lifestyle intervention.⁵⁴ Furthermore, lifestyle interventions, including exercise and/or diet have multiple anti-inflammatory effects that extend well beyond that of just reducing CRP. Exercise and diet are probably best suited for treating individuals with elevated inflammatory markers. Even modest changes in exercise and diet can produce favorable long-term changes in biomarkers of inflammation.¹¹⁶ Both aerobic and resistance type exercise have been found to improve inflammatory status, with the majority of evidence suggesting that aerobic exercise may have broader anti-inflammatory effects. Intensive lifestyle interventions involving both exercise and diet appear to be most effective.

A number of dietary factors, including fiber-rich foods, whole grains, fruits (especially berries), omega-3 fatty acids, antioxidant vitamins (eg, C and E), and certain trace minerals (eg, zinc) have been documented to reduce inflammatory markers. Additionally, anti-inflammatory foods may help mitigate the pro-inflammatory postprandial state that is particularly evident after ingestion of meals high in saturated fat. Intensive lifestyle interventions involving both exercise and diet appear to be most effective. For the most part, anti-inflammatory effects of exercise and diet are independent of weight loss. Thus, overweight and obese men and women, who are more likely to have a pro-inflammatory profile, do not necessarily have to normalize body mass index to improve inflammatory status and reduce risk of chronic diseases such as T2D and CVD.

Footnotes

*

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Lifestyle Measures to Reduce Inflammation

Abstract

Keywords

Exercise and Inflammation

Aerobic Exercise Interventions

Resistance Exercise Interventions

Combined Aerobic and Resistance Exercise Interventions

Dietary Factors to Treat and Prevent Inflammation

Dietary Fiber

Berries

Omega-3 (n-3) Unsaturated Fatty Acids

Vitamin E

Zinc

Reduced Intake of Saturated Fatty Acids

Postprandial Inflammation

Dietary Strategies to Mitigate Postprandial Inflammation

Combined Exercise and Dietary Interventions to Reduce Inflammation

Potential Mechanisms for Improved Inflammatory Status With Lifestyle Intervention

Exercise and/or Diet Effect Is Independent of Weight/Fat Loss

Reduction in Adipose Tissue Hypoxia

Conclusions

Footnotes

*

References