Exercise and Diet, Independent of Weight Loss

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CLINICAL FOCUS: DIABETES AND OBESITY

Exercise and Diet, Independent of Weight Loss, Improve Cardiometabolic Risk Profile in Overweight and Obese Individuals

Glenn A. Gaesser, PhD 1 Siddhartha S. Angadi, BOTh 1 Brandon J. Sawyer, MEd 1 1 Healthy Lifestyles Research Center, College of Nursing and Health Innovation, Arizona State University, Mesa, AZ

Abstract Diet and/or exercise are routinely advised as methods for weight loss in overweight/obese individuals, particularly those who are at high risk for cardiovascular disease and type 2 diabetes mellitus. However, physical activity and structured exercise programs rarely result in significant loss of body weight or body fat, and weight-loss diets have extraordinarily high recidivism rates. Despite only modest effects on body weight, exercise and ad libitum nutrient-dense diets for overweight/obese individuals have many health benefits, including skeletal muscle adaptations that improve fat and glucose metabolism, and insulin action; enhance endothelial function; have favorable changes in blood lipids, lipoproteins, and hemostatic factors; and reduce blood pressure, postprandial lipemia and glycemia, and proinflammatory markers. These lifestyle-induced adaptations occur independently of changes in body weight or body fat. Thus, overweight/obese men and women who are at increased risk for cardiovascular disease and type 2 diabetes as a result of sedentary lifestyle, poor diet, and excess body weight should be encouraged to engage in regular physical activity and improve their diet, regardless of whether the healthier lifestyle leads to weight loss. Keywords: exercise; physical activity; diet; lifestyle; obesity; diabetes

Introduction

Correspondence: Glenn A. Gaesser, PhD, Healthy Lifestyles Research Center, Arizona State University, 7350 E. Unity Ave., Mesa, AZ 85212. Tel: 480-727-1944 Fax: 480-727-1051 E-mail: [email protected]

Weight loss has been the primary treatment goal for individuals who are overweight or obese, particularly those with type 2 diabetes mellitus and/or cardiovascular comorbidities. A weight loss of approximately 10% of initial body weight has been recommended as an initial target goal.1,2 This goal is often difficult to achieve through lifestyle interventions,3 and studies of long-term weight-loss maintenance indicate high recidivism rates.4 Because the prevalence of weight-loss attempts among US adults is so high (46% for women; 33% for men),5 this sets the stage for a pattern of chronic weight fluctuation that may be harmful.6–8 Consequently, lifestyle interventions have been advocated that focus more on behavior (eg, exercise and diet) than weight loss.9–11 There is considerable support for a non–weight loss-centered paradigm, which shows that many obesity-related health conditions can be substantially improved through changes in exercise and diet and are independent of weight loss (Table 1). This paradigm also predicts that increasing physical activity and improving the quality of a diet should have a far more beneficial impact on premature mortality than weight loss.10 In establishing an evidence-based approach for this paradigm, we fully acknowledge the documented benefits of weight loss in obese, at-risk populations.1,2,12–19 However, because individuals who lose weight

© The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847

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tend to gain it back,4 alternative approaches to treatment of excess body weight and associated comorbidities are warranted. Table 1. Health Benefits of Exercise and/or Diet for Overweight and Obese Individuals, Independent of Changes in Body Weight or Body Fat Glucose metabolism and insulin action Decreased fasting glucosea Decreased fasting insulinb Increased glucose tolerancec Increased insulin sensitivityd Decreased HbA1ce Blood pressure Decreased resting systolic blood pressuref Decreased resting diastolic blood pressureg Decreased ambulatory blood pressure30,55,56 Lipids and lipoproteins Decreased cholesterolh Decreased LDL-C or oxidized LDLi Increased HDL-Cj Decreased triglyceridesk Improved lipid subfractions33,61,64n,98 Endothelial function Increased vascular dilatory functionl Hemostasis Increased tissue plasminogen activator release capacity83 Fibrinolytic control83 Decreased fibrinogen28 Decreased plasminogen activator inhibitor-134n Decreased MMPs28,82 Increased MMP inhibitors (tissue factor pathway inhibitors)28 Tissue factor pathway inhibitor57n Inflammation Increased anti-inflammatory markers29,44 Decreased proinflammatory markersm Skeletal muscle adaptations Mitochondrial enzyme increase in number and activation22,39,42,94 Increased mitochondrial fat oxidation22,39,42,94 Decreased muscle diacylglycerol content22 Decreased muscle ceramide content22 Postprandial metabolism Decreased lipemia43,97,98 Decreased glycemia24,43 a

References 24,28–30,31n,32n,33,34n,35,36n References 22–24,26,27,29,30,32n,37–39 c References 22–27 d References 22,23,25–27,29,30,31n,32n,36n,37,38,40–43 e References 24,28,29,33,44,45 f References 24,29,30,31n,36n,44o,54,56,57–59n,60o,101 g References 24,28,30,31n,36n,44o,54,56,58n,59n,60n,76n h References 28,29,31n,32n,33,44o,60o,64n,65n,67o i References 27–29,31n,34n,60o,65n,66n,67o j References 24,29,30,31n,32n,36n,44,60o,62,89 k References 24,27,29,30,31n,32n,33,60o,61,62,64n,67o,89,97,98 l References 63,72–75,76–78n,99 m References 31n,32n,35,36n,44,82,89,90,91–93n,98 n Diet intervention o Exercise and diet intervention. Abbreviations: HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; MMPs, matrix metalloproteinases. b

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This article briefly describes the relevant research that shows that in overweight/obese individuals, either with (or who are at risk for) type 2 diabetes and/or cardiovascular disease (CVD), cardiometabolic risk markers can be improved, if not entirely ameliorated, through lifestyle intervention, independent of weight loss. This non–weight loss-centered approach may provide physicians with a strong rationale for prescribing exercise and a healthier diet to overweight/obese patients, for whom sustained weight loss has often proved unattainable.

Reduction in Type 2 Diabetes Risk Lifestyle interventions that include weight loss as a goal have been reported to reduce incidence of type 2 diabetes.15–19 In both the Diabetes Prevention Program (DPP) and Finnish Diabetes Prevention Study (FDPS), mean weight loss after 3 to 4 years of intervention averaged approximately 3 to 4 kg, and type 2 diabetes risk was reduced by 58%.15,16 Subsequent analyses indicated that weight loss was the dominant predictor of reduced type 2 diabetes incidence in both of these interventions.18,19 However, weight loss may not be necessary to reduce the incidence of type 2 diabetes. Two more recent lifestyle intervention programs revealed significant reductions in type 2 diabetes incidence with either no weight loss20 or only minor weight loss (1.08 kg).21 In the PREDIMED trial, a Mediterranean diet was supplemented with either virgin olive oil or nuts. Over a 4-year period, type 2 diabetes incidence was reduced by 52% compared with a control, low-fat diet group.20 Similarly, in the 3-year Study of Lifestyle Intervention and Impaired Glucose Tolerance Maastricht (SLIM),21 the lifestyle intervention group experienced a 58% reduction in type 2 diabetes incidence despite a mean weight loss of only 1.08 kg. These reductions in type 2 diabetes incidence are comparable with those observed in the DPP and FDPS, yet weight loss was either much less or entirely absent. Thus, lifestyle interventions may be effective in reducing type 2 diabetes in at-risk populations, even when body weight remains largely unchanged. We contend that reductions in type 2 diabetes risk, in the absence of weight loss, are largely due to the beneficial effects of exercise and/ or improved diet on glucose metabolism and insulin action, independent of weight loss.

Glucose Metabolism and Insulin Action Aerobic exercise training, independent of changes in body weight, has been shown to significantly increase glucose tolerance,22–27 reduce fasting and postprandial glucose,24,28–36


Weight Loss-Independent Effects of Exercise and Diet

reduce fasting insulin,22–24,26,27,29,30,32,37–39 enhance insulin sensitivity,22,23,25–27,29–32,36–38,40–43 and reduce glycated hemoglobin (HbA1c)24,28,29,33,44,45 in overweight and obese individuals. In these studies, anthropometric indices were either unchanged or decreased minimally (eg, 2%), suggesting that loss of body fat was not a major factor in the adaptation. In fact, exercise training may enhance insulin sensitivity even when increasing adiposity after training.38 These findings may be partly explained by the fact that just 1 bout of exercise can improve insulin sensitivity,40,46 and that this effect may persist for up to 72 hours after exercise.40 It is well established that weight loss significantly improves glucose metabolism and insulin action in overweight and obese individuals.47–51 However, metabolic improvements associated with weight loss may be reversed during weight regain.52 In an observational study of obese men and women, improvement in insulin action and insulin secretion associated with a 10% weight loss was entirely reversed during weight regain.52 Because significant weight loss (∼10%) is difficult to maintain,3 the documented benefits of significant weight loss in risk management may be transient. Furthermore, instability of metabolic risk factor levels, such as insulin resistance (which can occur because of chronic weight fluctuation), has been reported to significantly predict atherosclerotic vascular disease during an 11.6-year period.6 For improving HbA1c, exercise training resulting in small to no amounts of weight loss appears to be just as effective as significant weight loss through calorie restriction. For example, a weight loss of 8 to 10 kg (8.6%) after 1 year in the Look AHEAD trial reduced HbA1c by 0.64%.47 In contrast, in a meta-analysis of 27 exercise training studies (5–52 weeks in duration) involving individuals with type 2 diabetes, it was revealed that exercise training decreased HbA1c by approximately 0.8%.24 The authors noted that this effect is similar to that observed with dietary, drug, and insulin treatments. Weight loss appeared to have little effect on the improvement in glycemic control because the improvement in HbA1c with aerobic exercise training alone (−0.7%) was about the same as that observed for combined aerobic and resistance exercise training (−0.8%), even though weight loss was much greater for the combined training (−5.1%) than for aerobic exercise training alone (−1.5%). A large randomized clinical trial of 251 adults with type 2 diabetes demonstrated that both aerobic and resistance training reduced HbA1c by 0.4% to 0.5%, but improvements were greatest for combined aerobic and resistance training (0.9%).45 Although combined training reduced HbA1c by twice as much as either mode alone, changes in body

weight (2.6 kg) and fat mass (1.6–1.9 kg) were the same for all groups. Both aerobic and resistance exercise training are effective for improving insulin sensitivity. Six months of either aerobic or resistance training in overweight/obese men increased glucose disposal by 20% to 25%, as assessed by a glycemic-hyperinsulinemic clamp.41 It is unlikely that reduced fat mass played a role because total fat mass remained unchanged after resistance training (+0.7 kg), yet was significantly reduced after aerobic exercise training (−2.1 kg). It has been suggested that changes in visceral adipose tissue that occur as a result of exercise training are responsible for the changes in insulin sensitivity.27 However, improvements in insulin sensitivity occur in the absence of reductions in visceral adipose tissue.41 In overweight/obese men and women who participated in the Studies of Targeted Risk Reduction Interventions Through Defined Exercise (STRRIDE), equal improvements in insulin sensitivity were achieved for both moderate- and vigorous-intensity programs despite greater reductions in visceral adipose tissue after the vigorous-intensity program.53 Dietary interventions that focus on improving diet quality also improve glucose metabolism and insulin action in the absence of clinically significant weight loss.31,32 In a 12-week dietary intervention in adults with type 2 diabetes or impaired fasting glucose, in which refined rice was replaced with whole grains and vegetable intake was increased, significant improvements in fasting glucose and Homeostasis Model of Assessment–Insulin Resistance (HOMA-IR) were observed, despite body mass index (BMI) decreasing by just 0.2 units.31 In a 3-month study of overweight/obese men and women at risk for CVD, it was demonstrated that when the participants consumed a Mediterranean diet for 3 months, fasting glucose and insulin were reduced and insulin sensitivity was improved, despite no statistically significant changes in body weight or weight circumference.32 After 4 years of follow-up, the Mediterranean diet reduced incidence of type 2 diabetes by 52%, despite no reduction in body weight.20

Blood Pressure Both aerobic and resistance exercise training have been shown to reduce resting and ambulatory blood pressure, with blood pressure improvements often occurring independently of weight loss.24,28–30,54–56 In a 6-week program in which 168 overweight men and women with stage I hypertension participated in brisk walking, 24-hour ambulatory systolic and diastolic blood pressures were reduced (systolic, from 143.1 to 135.5 mm Hg; diastolic, from 91.1 to 84.8 mm Hg)


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without reducing body weight.55 A meta-analysis of 72 exercise intervention trials found that training reduced resting and ambulatory blood pressure in normotensives by approximately 3 to 4 mm Hg and in individuals with hypertension by approximately 5 to 7 mm Hg.30 These improvements occurred despite minimal changes in body weight (∼1.2 kg) and percent body fat (∼1.4%). Correlations between changes in BMI, systolic blood pressure (r = 0.09), and diastolic blood pressure (r = 0.07) are extremely low,54 suggesting that decreases in BMI explain 1% of the changes in blood pressure with exercise training. Resistance exercise also lowers blood pressure in overweight and obese individuals. In a meta-analysis by Kelley,56 it was demonstrated that resistance training in both normotensive and hypertensive individuals resulted in a 3% to 4% reduction in blood pressure with no significant changes in body weight. Improvements in the quality of diet can lower blood pressure without any significant weight loss.32,36,57–59 This is best exemplified by the Dietary Approaches to Stop Hypertension (DASH) trial.58 Specifically designed to assess the impact of diet on blood pressure in the absence of weight loss, the DASH diet reduced both systolic (−5.5 mm Hg) and diastolic (−3.0 mm Hg) blood pressure. Among 133 men and women with hypertension, consuming more fruits and vegetables, as well as dairy foods low in saturated fat, was sufficient to reduce systolic blood pressure by an average of 11.4 mm Hg, and diastolic blood pressure by an average of 5.5 mm Hg in a 2-week period.58 The reductions in blood pressure were comparable with those observed with administration of pharmacotherapy. More significantly, the reductions in blood pressure were achieved without any weight loss. The DASH diet is associated with an increased intake of potassium and magnesium, and these have been linked to reduced blood pressure. In a recent study, however, supplementing patients’ usual diets, which are usually low in fruits and vegetables, with diets rich in potassium and magnesium to match those of the DASH diet, did not lower blood pressure by as much as the DASH diet alone, suggesting that the blood pressure-lowering effect of the DASH diet extends beyond any impact attributable to potassium and magnesium.59 Even when weight loss occurs with exercise and/or noncalorically restricted dietary interventions that lower blood pressure, the amount of weight loss is modest and correlates weakly, if at all, with the magnitude of blood pressure reduction.60 In a combined exercise and diet intervention, results showed an 18.8-mm Hg decrease in systolic blood pressure and an 8.0-mm Hg decrease in diastolic blood pressure.60 Weight loss was modest (4 kg; 3.7%) and

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was not associated with the magnitude of blood pressure reduction. For comparison, in the Look AHEAD trial of intentional weight loss, an 8.6% reduction in body weight reduced systolic blood pressure by 6.8 mm Hg and diastolic blood pressure by 2.9 mm Hg.47 In a meta-analysis of weight loss interventions in patients with type 2 diabetes, a weight loss of 9.6% (9.2 kg) was associated with decreases of 8.1% (∼11 mm Hg) and 8.6% (∼7 mm Hg) for systolic and diastolic blood pressure, respectively.12

Lipids and Lipoproteins Exercise training appears to have diverse, somewhat inconsistent effects on serum levels of lipids and may vary by modality. In general, however, it has favorable effects on lipids and lipoproteins, even in the face of unchanged body weight24,28–30,33,44 or clinically insignificant weight loss ( 2%).53,61 A meta-analysis of 27 studies concluded that aerobic exercise was associated with a small but statistically significant effect on increasing high-density lipoprotein cholesterol (HDL-C) levels and exhibited a trend toward decreasing serum triglyceride levels.24 Another meta-analysis of 72 studies indicated a small but statistically significant effect of aerobic exercise on increasing HDL-C, and a trend (P = 0.07) for a reduction in triglycerides; overall changes in body mass (∼1.2 kg) and body fat ( 2.0%) were small.30 In 1 study of Asian Indians with type 2 diabetes, Misra et al33 reported that 12 weeks of resistance exercise training reduced total cholesterol (8.5%), triglycerides (19.6%), and very low-density lipoprotein cholesterol (LDL-C) (32.1%), with no changes in BMI or total body fat. In a randomized trial carried out on overweight, sedentary, and dyslipidemic men and women, 8 months of exercise training (varying in amount and intensity) improved 11 different lipid and lipoprotein variables in the absence of clinically significant weight loss ( 1.52 kg).61 Aerobic exercise may be of particular value in treating individuals with the most atherogenic lipids profiles. In 1 study, 20 weeks of aerobic exercise training was more effective at improving lipid and lipoprotein profiles in overweight men with a combination of low HDL-C and elevated triglycerides than in men with either isolated low HDL-C or elevated triglycerides.62 High-density lipoprotein cholesterol was increased by 4.9% and triglycerides were reduced by 15%, despite small changes in weight (−0.7 kg) and fat mass (−1.1 kg). Similarly, in both overweight/obese adults with and without type 2 diabetes, an 8-week program of aerobic exercise significantly reduced total cholesterol



(8%–13%) and LDL-C (13%–19%), and increased HDL-C/ total cholesterol (10%–17%), but did not significantly alter body weight or fat mass.63 A number of dietary interventions show that lipid profile can be improved independently of weight loss.31,32,64–66 In patients with type 2 diabetes, Chandalia et al64 reported that the addition of 26 g per day of soluble and insoluble fiber to the American Diabetes Association diet for 6 weeks reduced total cholesterol (−14 mg/dL), triglycerides (−21 mg/dL), and very LDL-C (−5 mg/dL) without demonstrating any changes in body weight. Chung et al31 also demonstrated that replacing refined rice with whole grains and increasing vegetable intake for 12 weeks reduced triglycerides, total cholesterol, and LDL-C, and increased HDL-C in patients with type 2 diabetes, though only a modest (0.4 kg) decrease in body weight was achieved. Combined diet and exercise interventions may be superior to either exercise or diet alone.60,67 Among 4587 men and women at risk for CVD, 3 weeks of consuming an ad libitum low-fat, high-complex-starch, high-fiber diet, in combination with daily moderate-to-vigorous aerobic exercise, reduced cholesterol by 23% (from 234 to 180 mg/ dL), LDL-C by 23% (from 151 to 116 mg/dL), and triglycerides by 32.5% (from 200 to 135 mg/dL).67 Although this intervention reduced body weight (4%–5%) by more than the interventions mentioned above, correlations between changes in lipids and changes in body weight ranged between 0.07 and 0.17, suggesting that very little of the decrease in cholesterol or triglycerides could be attributed to decreases in body weight. For comparison, studies of intentional weight loss in obese men and women indicate that weight loss of 8% to 10% reduces total cholesterol by approximately 9%, LDL-C by 5% to 11%, and triglycerides by 16% to 27%.12,47 Greater weight loss (∼15%) may reduce triglycerides by even more (44.5%).13 In 1 study, however, weight loss itself was found to be a weak predictor of reductions in triglycerides (r = 0.18).13

Endothelial Function Endothelial function appears to play a key role in the pathogenesis of atherosclerosis and is considered the first step in the genesis of atherosclerosis. It is also a strong and independent predictor of cardiovascular morbidity and mortality.68 It has been suggested that weight loss of approximately 10% may be necessary to significantly improve endothelial function.69,70 In overweight/obese adults, weight loss of 10.6% improved brachial artery flow-mediated dilation (FMD) by 30%.69 Among severely obese patients who lost

27.6% body weight by diet and/or bariatric surgical intervention, brachial artery FMD was improved by 47%.71 However, both aerobic and resistance exercise training, in the absence of weight loss, have been reported to improve endotheliumdependent vasodilation in a number of populations.63,72–74 In men and women with metabolic syndrome, 12 weeks of either aerobic interval training, resistance exercise training, or combined training increased brachial artery FMD by 28% to 38% in all groups, despite no change in body weight.73 Although both aerobic and resistance training groups reduced body fat modestly (1.9–2.1 kg; 6%–7%), the combined training group had no statistically significant reduction in body fat (0.8 kg; 2.4%), yet had the greatest improvement (∼38%) in brachial artery FMD. This suggests that the reduction in body weight or body fat was not responsible for the improvements in endothelial function. In 1 study, a 1-year period of resistance exercise training in overweight women was reported to increase brachial artery FMD by 41%, without a reduction in total body fat mass.72 In 1 study, it was demonstrated that 8 weeks of aerobic exercise training increased forearm vasodilatory response to acetylcholine by 56% in overweight men and women and by 41% in obese men and women with type 2 diabetes, despite there being no changes in body weight or fat mass.63 In obese adults with type 2 diabetes, 4 weeks of aerobic training and a hypocaloric diet reduced body weight by 6.1% (6 kg), but had no effect on coronary vasodilation.75 Interestingly, after an additional 5 months of training, during which time body weight had increased by 3.1 kg (ie, ~50% weight regain from the 4-week weight-loss peak), coronary blood flow in response to acetylcholine infusion increased by 127% and, in response to adenosine infusion, increased by 58.7%. Such significant improvements in coronary endothelial function achieved during a period of weight gain of 3.1 kg suggests that exercise training may be more important than weight loss for improving vascular health. Three months of close adherence to a Mediterranean diet improved brachial artery FMD by 50% in abdominally obese adults.76 The modest (2.7 kg; 2.9%) weight loss achieved after the intervention likely did not explain the results because a comparison diet group lost a similar amount of weight (2.1 kg; 2.2%) yet experienced no change in endothelial function. In an 8-week study of obese men and women with type 2 diabetes, an ad libitum diet supplemented with walnuts (56 g/day) resulted in a 25.6% increase in brachial artery FMD, despite no changes in body weight or waist circumference.77 The suggestion that diet quality is more important than weight loss itself is exemplified by the fact that a low-carbohydrate diet


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has been reported to induce weight loss but impairs endothelial function.78 In overweight or obese men and women, a 1-year period of a low-carbohydrate diet reduced body weight by 14.9 kg (15.8%), yet impaired brachial artery FMD by 35%.78

Hemostasis Type 2 diabetes and CVD result in an inability to degrade arterial plaque and control blood coagulation. Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are a family of endopeptidases that have proteolytic properties.79 Data on humans suggest that MMP-2 and MMP-9 can mediate atherogenesis, control plaque disruption, and cause plaque hypercoagulability.80 In a 16-week, home-based aerobic exercise intervention of 150 minutes per week in 25 sedentary, overweight subjects with type 2 diabetes, MMP-9 was reduced by 32% and TIMP-2 was increased by 18%.28 Furthermore, the intervention lowered the MMP-9/ TIMP-1 ratio by 33%, which is an independent predictor of coronary artery disease (CAD) severity.81 The improvements seen in pro- and antiatherogenic markers were combined with a 17% decrease in fibrinogen and a 30% decrease in C-reactive protein (CRP), despite no change in BMI.28 Similarly, 12 weeks of supervised endurance exercise in patients with known CAD and/or CVD risk factors reduced MMP-9 by 18%, with only a very modest reduction in BMI (0.4 units).82 For comparison, weight loss of 12% to 13% (13–15 kg) after 8 weeks on a very low-energy diet with or without orlistat increased MMP-9 by 23%.51 After 3.2 years of follow-up in this study, sustained weight loss of 6% to 9% was associated with reduction in MMP-9 from a baseline of 17% to 34%,50 which is comparable with the reductions seen with endurance exercise training, with no change28 or modest (1.5%) change82 in BMI. Overweight and obese individuals typically have impaired endothelial control of fibrinolysis, particularly because of insufficient release of tissue plasminogen activator. In a study of overweight and obese adults, 3 months of aerobic exercise training (40–50 min at 60%–75% maximal heart rate, 5–7 days/week) improved tissue plasminogen activator release by 55%, to the same levels as nonoverweight controls.83 The training did not reduce body weight, body fat, or waist circumference, which suggests that the impaired fibrinolytic control was linked to the sedentary lifestyle and not the excess body weight.83 We are unaware of any effect of weight loss on vascular endothelium tissue plasminogen activator release. Dietary modifications with little to no weight loss have also been shown to improve hemostatic factors in diseased

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populations.34,57 In a sample of 49 asymptomatic subjects at high risk for CVD, Llorente-Cortés et al57 found that when patients consumed a Mediterranean diet with added nuts and that was high in monounsaturated fatty acids, polyunsaturated fatty acids, and various bioactive compounds for a 3-month period, this tissue factor pathway inhibitor was increased by by 39%, despite no changes in body weight. Tissue factor pathway inhibitor is known to decrease blood coagulation and reduce restenosis of arteries.84,85 The authors concluded that a Mediterranean diet with added nuts may cause vascular remodeling.57 In contrast, tissue factor pathway inhibitor activity was decreased by 7% after weight loss of 32% via gastroplasty.86 Plasminogen activator inhibitor-1 (PAI-1), which inhibits the activation of fibrinolysis, has been shown to increase in obese populations.48 In 1 study, 10 weeks of a low-glycemic diet decreased PAI-1 by 15% in overweight women, despite minimal weight loss (−1.9 kg).34 The fact that PAI-1 activity was not changed in women who consumed a high-glycemic diet, despite similar weight loss (−1.3 kg), suggests that the improvement was attributable to diet quality rather than weight loss itself. However, substantially greater diet-induced weight loss (8%–10%) has been shown to reduce PAI-1 by 31% to 38%, which suggests that weight loss does play a role.48,51 It is important to note that the addition of exercise to a hypocaloric diet produced a 71% reduction in PAI-1,48 which suggests that both exercise and weight loss are contributing factors. Adipose tissue hypoxia associated with obesity has been shown to result in increased gene expression of PAI-1 in cell lines.87 Adipose tissue hypoxia can be ameliorated by both weight loss and exercise.87 At this point, however, it is not clear if one strategy is superior to the other.

Inflammation Cardiovascular disease and type 2 diabetes have been shown to be characterized by low-grade inflammation.88 Lowgrade inflammation is detected by elevations in numerous pro-inflammatory biomarkers, including CRP, interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-18, IL-1β, interferon-γ (IFN- γ ), CD14+, CD16+, CD49d, CD40, and E-selectin, or by lower levels of anti-inflammatory biomarkers such as IL-4, IL-10, and adiponectin. Although weight loss has been reported to affect inflammatory molecules, it has been demonstrated that inflammatory status can be improved with exercise and/or diet in the absence of weight loss.29,32,35,36,44,82,89–93 In a study of men and women with type 2 diabetes, 12 months of either aerobic or combined aerobic and resistance exercise training significantly reduced CRP, IL-1β,



IL-6, TNF-α, and IFN-γ, and increased IL-4, IL-10, and adiponectin.44 Body weight was not reduced in either group, indicating that exercise training has a full anti-inflammatory effect that is indepdendent of weight loss.44 In contrast, significant weight loss (9%–10%) after a hypocaloric diet did not reduce CRP.49,51 As a result, Madsen et al49 concluded that weight loss of 10% is necessary to significantly improve inflammatory markers in obese individuals. However, in a study of overweight men and women with type 2 diabetes, 6 months of aerobic training (4 days/week, 45–60 min/session at 50%–75% peak oxygen consumption) reduced CRP by 39%, IL-18 by 35%, and IL-18/ IL-10 ratio by 50%, and increased anti-inflammatory marker IL-10 by 43%.29 Body weight and fat mass were not reduced. The weight-loss–independent effect of exercise training is best exemplified by Milani et al,89 who studied 235 patients with coronary heart disease before and after cardiac rehabilitation. Patients who lost weight (6 lb; 3% of initial body weight) reduced their CRP levels by 31%; patients who gained weight (6 lb; 3% of initial body weight) also reduced their CRP levels by 42%. Furthermore, Lambert et al90 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 reduced Toll-like receptor-4 mRNA by 37% and IL-6 and TNF-α mRNA by 50%. Thus, body weight/body 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. Dietary interventions, in the absence of weight loss, have also been shown to improve inflammatory status.32,36,91–93 In overweight/obese adults at high risk for CVD, 3 months of a Mediterranean diet supplemented with either virgin olive oil (1 L/week) or nuts (30 g/day) significantly reduced proinflammatory markers CD49d, CD40, and IL-6, with a reduction in CRP observed only in the diet supplemented with virgin olive oil.36 Both diets also significantly reduced IL-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1.32 Body fat was unchanged. Similarly, studies that replaced typical Western protein products high in saturated fats (ie, red meat) with other protein-rich foods (eg, soy92 and almonds93) have shown decreases in proinflammatory markers, including E-selectin,92,93 IL-18,92 and CRP,92,93 yet there were no changes in body weight.

mitochondrial function, and increases in capillarization, which are highly related to improvements in insulin sensitivity as well as carbohydrate and lipid disposal.22,39,42 Two recent studies demonstrated that 12 weeks of combined resistance and endurance exercise training in overweight/ obese men with type 2 diabetes restored mitochondrial function to the level of healthy control subjects, despite there being no changes in body weight and only minimal changes in body fat ( 1.5 kg).39,42 In vivo mitochondrial function was significantly lower in the type 2 diabetes group before training, but improved by 48% after 12 weeks of training to a similar level as the control group. In addition, insulin sensitivity was increased by 63%.42 In a subset of this population, ex vivo mitochondrial function was increased by 33% to a level that was not significantly different than that of the nondiabetic controls matched for age and BMI.39 Weight loss does not improve skeletal muscle mitochondrial capacity.94 However, 1 study demonstrated that just 10 consecutive days of aerobic exercise in both obese women and formerly obese women increased skeletal muscle fat oxidation capacity and the mRNA content for pyruvate dehydrogenase kinase-4, carnitine palmitoyltransferase 1, and peroxisome proliferator-activated receptor-γ coactivator-1α.94 Thus, skeletal muscle mitochondrial defects evident with obesity can be corrected with exercise training but persist after weight loss. Exercise training may also change lipid composition in skeletal muscle. In a study of 9 obese men and women, 8 weeks of moderate-intensity endurance training (five 60-min sessions/week at 65%–70% peak oxygen consumption) increased activities of several mitochondrial enzymes by 36% to 250%, and more than doubled (120% increase) skeletal muscle fatty acid oxidation.22 Additionally, training marginally (P = 0.06) reduced total muscle diacylglycerol content by 15% and saturated DAG content by 27%, and reduced total muscle ceramide content by 42% and saturated ceramide species by 32%. The reductions in diacylglycerol fatty acids were significantly correlated with improvements in insulin sensitivity, which is consistent with the view that muscle ceramide content may play a role in insulin resistance.95 These exercise training-induced reductions in skeletal muscle diacylglycerol and ceramide content occurred despite no reduction in body weight.

Skeletal Muscle Adaptations with Exercise Training

Postprandial Metabolism

Aerobic exercise training results in skeletal muscle adaptations, including increases in mitochondrial enzymes, overall

Exaggerated postprandial lipemia and decline in endothelial function due to a high-fat meal may be important factors


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in atherosclerotic plaque formation and development of metabolic syndrome. Both exercise and weight loss reduce postprandial lipemia, although much of the weight-loss effect may be due to negative energy balance rather than weight loss itself.96 Exercise training in the absence of weight loss reduces both fasting and postprandial triglyceridemia.97 Even acute exercise in the absence of habitual training improves the postprandial response to a high-fat meal.43,98,99 In obese men with metabolic syndrome, 60 minutes of exercise at either 40%, 60%, or 70% of maximal oxygen consumption performed 12 hours before ingestion of a fat-rich meal attenuated postprandial triglyceridemia by 30% to 40%.43 These postprandial reductions in triglycerides after 1 exercise session are comparable with those observed after 7 weeks of exercise training,97 suggesting that much of the apparent training adaptation may be due to the effects of the most recent exercise session. Although acute exercise may not always attenuate postprandial triglyceridemia, exercise may provide protection against endothelial dysfunction that is typically observed following ingestion of a high-fat meal.99 In overweight men, 1 session of high-intensity aerobic interval exercise 16 hours prior to ingestion of a high-fat meal completely abolished the impairment in endothelial function that occurred after ingestion of the high-fat meal without prior exercise.99 The mechanism may be linked to blood total antioxidant status, as this was highly correlated (r = 0.90) with postprandial brachial artery FMD.

Conclusion The marked improvements in cardiometabolic risk profiles of overweight and obese individuals accompanying exercise and diet interventions, even in the absence of clinically significant weight loss, may help to explain the findings in a number of observational studies that aerobic fitness greatly attenuates mortality risk in overweight/obese individuals.100 A recent review demonstrated that the risk for all-cause and CVD-related mortality was lower in individuals with high BMI and good aerobic fitness compared with individuals with normal BMI and poor fitness.100 The importance of these findings must be viewed in the context of the poor results of weight-loss interventions and long-term weight maintenance.3,4 Although the cardiovascular and metabolic benefits of weight loss in overweight/obese patients are well documented,1,2,12–19,47–50 the high recidivism rates for weight-loss interventions4 suggest that these benefits are not sustained.52 In the past 30 years, the prevalence of obesity has doubled; in addition, the prevalence of weight-loss attempts (mostly

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via calorie restriction) has remained consistently high.5 An estimated 60% to 70% of obese men and women in the United States attempt weight loss each year.5 Thus, calorie restriction approaches to weight management do not appear to have been very successful. Furthermore, the weight fluctuation that typifies chronic attempts to lose weight may not be benign.6–8 Instability of metabolic risk factors (eg, fasting insulin, non–HDL-C/HDL-C ratio) has been reported to be a significant predictor of atherosclerotic vascular disease,6 which may explain in part the higher CVD mortality rate associated with weight fluctuation.8 Although weight loss is a desired outcome for many overweight/obese persons, we contend that it may be more prudent to focus on increasing physical activity and improving diet quality rather than focusing on a specific weight-loss goal. For example, data from the FDPS15 and DPP16 indicate that 50% to 100% more participants were able to achieve the physical activity target (150 min/week in the DPP; 210 min/week in the FDPS) than were able to achieve the weight-loss goal ( 7% loss of initial body weight in the DPP; 5% loss of initial body weight in the FDPS). Thus, for at-risk populations (eg, sedentary individuals with a high BMI), it may be easier to increase fitness than to decrease fatness. Most of the beneficial adaptations to exercise training described in this article can be attained with relatively moderate-intensity effort, equivalent to brisk walking.10,22,30,37,43,54,55,72 This is particularly true for improving glucose metabolism and insulin action,37 and for lowering blood pressure.30,54 It is also important to emphasize that exercise training adaptations can occur rapidly, within 7 to 10 days,26,94 and that even single exercise sessions have acute benefits that can persist for hours (eg, blood pressure reduction101) or days (eg, enhanced insulin action40). Exercise sessions as short as 10 minutes can lower blood pressure, and fractionizing exercise bouts into multiple 10-minute sessions per day may be more effective than a single 30-minute session of exercise for lowering systolic blood pressure throughout the day.101 Similarly, dietary strategies that focus on increasing consumption of nutrient-dense foods (eg, fruits, vegetables, whole grains, and nuts) without an arbitrary weight-loss goal, such as the DASH58,59 and Mediterranean20,32,36,66,76 diets, may produce more long-lasting health benefits and avoid the pitfalls of calorie-restrictive approaches that may lead to chronic weight fluctuation. Because there does not appear to be a clinically significant minimum level of weight-loss that must be reached to produce clinical benefits,14 specific weight loss goals may be unnecessary. Indeed, the mere intention to lose weight,



even if unsuccessful, has been reported to be associated with a reduction in 9-year mortality risk in overweight adults with type 2 diabetes.102 This might be explained by the adoption of a healthier lifestyle that did not induce weight loss. From a public health perspective, it is essential to emphasize that overweight/obese individuals with risk factors for type 2 diabetes and CVD can reap important cardiometabolic benefits from physical activity and healthy eating regardless of changes in adiposity. Thus, overweight/ obese individuals considered at increased risk for CVD and type 2 diabetes due to sedentary lifestyle, poor diet, and a high BMI should be encouraged to engage in regular physical activity and consume a more nutrient-dense diet, regardless of whether the healthier lifestyle leads to weight loss.

Conflict of Interest Statement Glenn A. Gaesser, PhD, Siddhartha S. Angadi, BOTh, and Brandon J. Sawyer, MEd disclose no conflicts of interest.

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