**4. Reduction of dyslipidemia induced by stress: Physical exercise and nutritional intervention**

The role of stress in the etiology of chronic degenerative diseases is increasingly recognized (Gerber & Pühse, 2009; Holmes et al., 2010; Tsatsoulis & Fountoulakis, 2006; Yin et al., 2005). Moreover, it has been reported that obese people have an exaggerated response to stress, which may further increase the risk of weight gain, leading to the development of insulin resistance, hyperlipidemia, diabetes mellitus, hypertension and atherosclerosis in both men and women. This burden of chronic degenerative diseases is strongly influenced by several lifestyle factors, including the way an individual perceives a stressful situation, i.e., "mental fitness" and also his/her general physical condition or "physical fitness" (McEwen, 1998).

Tsatsoulis & Fountoulakis, 2006, demonstrated that stress-mediated allostatic load, in the presence of physical inactivity, is associated with an increased risk of mental and physical illness, and direct evidence for this notion has been provided by several studies. A strong inverse association between physical activity and the metabolic syndrome has been demonstrated, and several years ago this association was shown to be much steeper in unfit individuals (Kriska et al., 1993; Lindgärde & Saltin, 1981). Evidence for this view was also provided by the MacArthur studies of successful aging based on a large cohort of elderly men and women (Seeman et al., 1997), showing that subjects with low levels of physical and mental fitness had higher prevalence of cardiometabolic disease when compared with those with high fitness levels. Moreover, a strong association between physical inactivity, excessive food consumption, high-fat diet and increasing incidence of insulin resistance, Type 2 diabetes, (Hawley, 2004; Steanovv et al., 2011), development of obesity (Venables & Jeukendrup, 2009; Vessby, 2000) and depression (Win et al., 2011) has also been described in the literature. Considering that stress, physical inactivity, and aging (associated with declining physical activity and metabolic rate, coupled with an energy intake not matched to the declining need), in addition to a high-fat diet, are the very features of our current lifestyle, the incidence of this "stress-induced/exercise deficient" phenotype is becoming increasingly prevalent in modern society (Davy et al., 1996, Hawley, 2004, Poehlman et al., 1995, Schiut et al., 1998, Tsatsoulis & Fountoulakis, 2006).

Based on the above mentioned findings, it is reasonable to assume that physical inactivity may potentiate the stress-related allostatic load and comorbidities, since the energy substrate that is mobilized during stress is not oxidized but is stored in visceral fat depots. This adaptation creates a vicious cycle, in which perceived stress is also associated with decreased participation in several health behaviors including exercise, social behaviors, stress management/rest, and safety/environmental behaviors, as shown by Padden et al., 2011, in the study on health behavior of military spouses during deployment separation. In this context, physical exercise practiced as a non-pharmacological alternative, either with or without the association of pharmacological therapies, is very important, and a great deal of attention should be given to the barriers imposed, especially by mood disorders, including depression. Individuals in this

Therefore, if we can block or minimize the stress components that directly or indirectly induce atherogenesis, it will be possible to preserve the protective components of vascular function and structure, thereby developing new preventive and therapeutic possibilities. Figure 2 illustrates the putative mechanisms of the relations between stress, dyslipidemia,

The role of stress in the etiology of chronic degenerative diseases is increasingly recognized (Gerber & Pühse, 2009; Holmes et al., 2010; Tsatsoulis & Fountoulakis, 2006; Yin et al., 2005). Moreover, it has been reported that obese people have an exaggerated response to stress, which may further increase the risk of weight gain, leading to the development of insulin resistance, hyperlipidemia, diabetes mellitus, hypertension and atherosclerosis in both men and women. This burden of chronic degenerative diseases is strongly influenced by several lifestyle factors, including the way an individual perceives a stressful situation, i.e., "mental fitness" and also his/her general physical condition or "physical fitness" (McEwen, 1998). Tsatsoulis & Fountoulakis, 2006, demonstrated that stress-mediated allostatic load, in the presence of physical inactivity, is associated with an increased risk of mental and physical illness, and direct evidence for this notion has been provided by several studies. A strong inverse association between physical activity and the metabolic syndrome has been demonstrated, and several years ago this association was shown to be much steeper in unfit individuals (Kriska et al., 1993; Lindgärde & Saltin, 1981). Evidence for this view was also provided by the MacArthur studies of successful aging based on a large cohort of elderly men and women (Seeman et al., 1997), showing that subjects with low levels of physical and mental fitness had higher prevalence of cardiometabolic disease when compared with those with high fitness levels. Moreover, a strong association between physical inactivity, excessive food consumption, high-fat diet and increasing incidence of insulin resistance, Type 2 diabetes, (Hawley, 2004; Steanovv et al., 2011), development of obesity (Venables & Jeukendrup, 2009; Vessby, 2000) and depression (Win et al., 2011) has also been described in the literature. Considering that stress, physical inactivity, and aging (associated with declining physical activity and metabolic rate, coupled with an energy intake not matched to the declining need), in addition to a high-fat diet, are the very features of our current lifestyle, the incidence of this "stress-induced/exercise deficient" phenotype is becoming increasingly prevalent in modern society (Davy et al., 1996, Hawley, 2004, Poehlman et al.,

Based on the above mentioned findings, it is reasonable to assume that physical inactivity may potentiate the stress-related allostatic load and comorbidities, since the energy substrate that is mobilized during stress is not oxidized but is stored in visceral fat depots. This adaptation creates a vicious cycle, in which perceived stress is also associated with decreased participation in several health behaviors including exercise, social behaviors, stress management/rest, and safety/environmental behaviors, as shown by Padden et al., 2011, in the study on health behavior of military spouses during deployment separation. In this context, physical exercise practiced as a non-pharmacological alternative, either with or without the association of pharmacological therapies, is very important, and a great deal of attention should be given to the barriers imposed, especially by mood disorders, including depression. Individuals in this

Atherosclerosis is an inflammatory disease and stress contributes to its development.

**4. Reduction of dyslipidemia induced by stress: Physical exercise and** 

1995, Schiut et al., 1998, Tsatsoulis & Fountoulakis, 2006).

and atherosclerosis.

**nutritional intervention** 

condition are at disadvantage, since most of the time they lack the energy and motivation to exercise, and this overwhelming feeling of lethargy seems very difficult to shift (Chaput et al., 2011). In this situation, when psychological stress is not accompanied by physical activity (such as the fight or flight reaction) and by effective use and fast clearance of free fatty acids, triggered by stimulation of the sympathetic nervous system, these are converted into triglycerides by the liver and then circulate in the blood within the VLDL (Howard et al., 1993). In fact, this maladaptative situation can lead to the development of dyslipidemia, reflected by elevated plasma triglyceride and reduced HDL concentration, overproduction of VLDL-apolipoprotein (apo) B-100, decreased catabolism of apoB containing particles, and increased catabolism of HDL apoA-I particles (Watts et al., 2008; Watts et al., 2009).

While physical inactivity may potentiate the stress-induced allostatic load, there is accumulating evidence suggesting that the adoption of an active lifestyle, including exercise training, may play a protective role in stress system dysregulation, reducing vulnerability to stress, and possibly delaying or preventing the future development of comorbidities, such as dyslipidemia, hypertension and insulin resistance (Roberts & Barnard, 2005; Tsatsoulis & Fountoulakis, 2006). In addition, physical activity may induce favorable changes in traditional and emerging coronary heart disease biomarkers among individuals with, or at high risk of coronary heart disease (Chainani-Wu et al., 2011). Assuming that the stress response is a neuroendocrine mechanism that occurs in anticipation of physical action, it is reasonable to assume that physical activity should provide the vehicle to prevent or combat the somatic and emotional consequences of stress. Thus, physical activity may promote physical and psychological benefits that are involved in both the indirect action of exercise in reducing stress, and a direct effect on various metabolic functions of the body (McMurray & Hanckney, 2005).

The first rationale for using exercise as a stress reduction strategy was based on the crossstressor adaptation, a promising hypothesis first presented in the 1990s (Sothmann et al., 1996), which has not received strong support since the publication of recent meta-analyses (Forcier et al., 2006; Hamer et al., 2006; Jackson & Dishman, 2006). According to Chaput et al., 2011, the key question now is whether physical activity, which seems to modulate the level of stress, may interact in the relationship between stress and obesity. Different possible mechanisms have been proposed, suggesting that exercise training might protect against stress induced obesity. Regular exercise has been demonstrated to have positive effects on plasma lipid and lipoprotein profiles (Durstine et al., 2002) and these results may have a significant independent effect on HDL cholesterol (Thompson et al., 1988). During physical activity, exercise increases lipid oxidation and lipolysis to ensure an adequate oxygen supply (McMurray & Hanckney, 2005), increases the ability of muscle tissue to take up and oxidize nonesterified fatty acids, and increases muscle lipoprotein lipase activity (Eriksson et al., 1997). Although studies indicate that exercise training changes gene expression in adipose tissue in different ways, affecting some types of adipose tissue more than others (Company et al., 2010), the lowering of plasma triglycerides proves the effects of exercise on VLDL kinetics. Moreover, it is important to highlight that a single 90-min bout of whole body resistance exercise (Tsekouras et al., 2009) or 2h of cycling (Magkos et al., 2006) was proven to be enough to decrease fasting plasma VLDLtriglyceride concentrations by increasing VLDL-triglyceride removal from plasma. These results may be due to the increase in blood flow and hepatic insulin sensitivity associated with an increase in lipoprotein lipase activity.

In addition to its possible direct effect modulating the stress response, exercise training improves insulin sensitivity, which might counteract the insulin resistance state produced

Dyslipidemia Induced by Stress 379

2001, one of proposals evaluated was the effects of aerobic exercise training on blood lipids and the relationship between these effects and diet. The results showed that majority of physically active individuals had an increase in HDL cholesterol, but this could be changed if there was a concomitant reduction in fat intake. The association between low-fat diet and exercise reduces LDL and HDL-cholesterol levels. Furthermore, reductions in total cholesterol, LDL-cholesterol and triglyceride levels were less frequently observed. As regards body weight loss, there was considerable variability between the groups, ranging from 7.2 Kg in the group that was not exposed to dietary intervention to 17.9 Kg in the group that underwent dietary intervention. In addition, Rubenfire et al., 2011, demonstrated that the association between changes in diet and exercise was effective in reducing cardiovascular risk in patients with metabolic syndrome. In this study, the nutritional component was based on a Mediterranean food pattern, and all the participants were provided with the information needed to optimize their nutritional choices in order to improve blood lipid and glucose levels, decrease body weight and blood pressure, and decrease insulin resistance (Rubenfire et al., 2011). It has also been proposed that high-fiber diets protect against obesity and cardiovascular disease by lowering insulin levels (Ludwig et al., 1999). In obese men, the implementation of a high-fiber and low-fat diet associated with regular physical activity resulted in significant reductions in inflammation and dyslipidemia by reducing serum lipids, insulin, oxidative stress, leukocyte-

Dietary fat influences glucose and lipid metabolism by altering cell membrane function, enzyme activity, insulin signaling, and gene expression (Risérus et al., 2009; Yamazaki et al., 2011) and dietary fructose consumption appears to induce dyslipidemia, obesity (Stanhope et al., 2009) and hypertension (Cunha et al., 2007; Farah et al., 2006). A combination of social stress and high-fat diet resulted in a significant imbalance in lipid regulation associated with changes in the expression of hepatic genes, responsible for its regulation (Chuang et al., 2010). Therefore, clinical strategies based on low fat and sugar intake associated with increase in physical exercise have been used, and have contributed to reducing the risks of

Dyslipidemia induced by stress is part of the body's response to cope with stressors. The mobilization of lipids, glucose and proteins, allows the organs and tissues to maintain homeostasis and adapt to the stressor. Any deficiency in the activation of this mobilization of energetic fuels can compromise the survival of the individual. Therefore, the increase in blood lipids induced by stress is adaptive and it should return to normal levels when the stressor ends. However, when the stressor is maintained over a long period, the dyslipidemia induced by stress persists and may have deleterious effects, contributing to the occurrence of insulin resistance, obesity, hypertension and atherosclerosis. Considering that physical inactivity may potentiate these effects, the association of physical exercise and control of hypercaloric food consumption have been used in the treatment of dyslipidemia. Knowledge about the physiological mechanisms involved in the adaptive role of transient dyslipidemia induced by acute stress, and in the deleterious effects of sustained dyslipidemia induced by chronic stress is very important in the improvement and development of preventive and therapeutic approaches because in modern society we are

endothelial interactions (Roberts & Barnard, 2005).

developing coronary and metabolic diseases.

continuously exposed to stressors.

**5. Conclusion** 

by chronic hypercortisolemia (Tsatsoulis & Fountoulakis, 2006). Insulin secretion could then be reduced, and thereby, its deleterious impact on energy intake may be diminished. Moreover, exercise training improves glucose tolerance among non-diabetic, non-obese subjects with hypertriglyceridemia (Lampman & Schteingart, 1991) and enhances the oxidative capacity of skeletal muscle (Tsatsoulis & Fountoulakis, 2006). Together, these beneficial adaptations could prevent stress-induced fat deposition by routing the energy mobilized in response to the stressor toward oxidation rather than storage.

Apart from the protective effects of exercise on the physical and metabolic aspects related to stress, a number of psychological and cognitive benefits have also been reported in the literature. These include improvements in depression and anxiety scores and general improvement in mood, cognitive functioning (Callaghan, 2004; Tsatsoulis & Fountoulakis, 2006), well-being and self esteem, leading to a decrease in body fat, triglycerides, LDL/HDL cholesterol ratio in stressed patients (De Geus & Stubbe, 2007). Physical activity can improve mental health by reducing depressive symptoms in young men (McGale et al., 2011) and in patients with metabolic syndrome (Rubenfire et al., 2011). Moreover exercise induces the elevation of circulating brain derived neurotrophic factor, which is known to improve the health and survival of nerve cells, suggesting that exercise influences brain health (Yarrow et al., 2010). Using animal models, exercise has also been shown to induce antidepressant responses (Greenwood et al., 2003). In rats, swimming exercise induces a remission of anhedonic symptoms suggesting that exercise training might induce biological alterations similar to those provided by antidepressant drugs. In addition, exercise plays an important role in hippocampal protection from damage caused by exposure to glucocorticoids (Sigwalt et al., 2011). In this context, physical activity was able to stimulate the proliferation of hippocampal cells (Ehninger & Kempermann, 2003), promote alterations in synaptic plasticity, neurogenesis and synaptogenesis (Castrén, 2005), and may also be linked to increased levels of brain testosterone (Mukai et al., 2006).

Another beneficial effect of exercise is related to feeding behavior. Stressful situations have been shown to affect feeding behavior (Wallis & Hetherington, 2009) that result in increased energy intake through the stimulation provided by ingesting palatable foods that may serve as feedback signals that reduce the perception and discomfort of stress, thereby contributing to the development of dyslipidemia and obesity (Dallman et al., 2005). Moreover glucorticoids are associated with high neuropeptide Y secretion, which has an orexigenic activity and increases the intake of sugar- and fat-rich- comfort foods (Kuo et al., 2008) and can lead to a state of leptin resistance and elevated levels of this hormone (Zakrzewska et al., 1997). In this context, it has been demonstrated that physical activity has the potential to modulate appetite control by improving the sensitivity of the physiological satiety signalling system, by adjusting macronutrient preferences or food choices and by altering the hedonic response to food (Blundell et al., 2003). Indeed, dietary modification, associated with physical activity has been shown to exert significantly favorable effects on the treatment and prevention of stress-induced comorbidities, improving glycemia, blood pressure, body weight, fat distribution, and lipid profile, which in turn suggest that chronic degenerative diseases are largely preventable (Dagogo et al., 2010). Although exercise cannot change total cholesterol and LDL-cholesterol unless dietary fat intake is reduced, this result may be dependent on the amount of energy expenditure during exercise (Durstine et al., 2002). Furthermore, depending on the time that the exercise is performed (before or after ingestion of fatty foods), its acute responses related to improvement in lipoprotein metabolism may be different (Hashimoto et al., 2011). In a review of several studies realized by Leon & Sanchez

by chronic hypercortisolemia (Tsatsoulis & Fountoulakis, 2006). Insulin secretion could then be reduced, and thereby, its deleterious impact on energy intake may be diminished. Moreover, exercise training improves glucose tolerance among non-diabetic, non-obese subjects with hypertriglyceridemia (Lampman & Schteingart, 1991) and enhances the oxidative capacity of skeletal muscle (Tsatsoulis & Fountoulakis, 2006). Together, these beneficial adaptations could prevent stress-induced fat deposition by routing the energy

Apart from the protective effects of exercise on the physical and metabolic aspects related to stress, a number of psychological and cognitive benefits have also been reported in the literature. These include improvements in depression and anxiety scores and general improvement in mood, cognitive functioning (Callaghan, 2004; Tsatsoulis & Fountoulakis, 2006), well-being and self esteem, leading to a decrease in body fat, triglycerides, LDL/HDL cholesterol ratio in stressed patients (De Geus & Stubbe, 2007). Physical activity can improve mental health by reducing depressive symptoms in young men (McGale et al., 2011) and in patients with metabolic syndrome (Rubenfire et al., 2011). Moreover exercise induces the elevation of circulating brain derived neurotrophic factor, which is known to improve the health and survival of nerve cells, suggesting that exercise influences brain health (Yarrow et al., 2010). Using animal models, exercise has also been shown to induce antidepressant responses (Greenwood et al., 2003). In rats, swimming exercise induces a remission of anhedonic symptoms suggesting that exercise training might induce biological alterations similar to those provided by antidepressant drugs. In addition, exercise plays an important role in hippocampal protection from damage caused by exposure to glucocorticoids (Sigwalt et al., 2011). In this context, physical activity was able to stimulate the proliferation of hippocampal cells (Ehninger & Kempermann, 2003), promote alterations in synaptic plasticity, neurogenesis and synaptogenesis (Castrén, 2005), and may also be linked to

Another beneficial effect of exercise is related to feeding behavior. Stressful situations have been shown to affect feeding behavior (Wallis & Hetherington, 2009) that result in increased energy intake through the stimulation provided by ingesting palatable foods that may serve as feedback signals that reduce the perception and discomfort of stress, thereby contributing to the development of dyslipidemia and obesity (Dallman et al., 2005). Moreover glucorticoids are associated with high neuropeptide Y secretion, which has an orexigenic activity and increases the intake of sugar- and fat-rich- comfort foods (Kuo et al., 2008) and can lead to a state of leptin resistance and elevated levels of this hormone (Zakrzewska et al., 1997). In this context, it has been demonstrated that physical activity has the potential to modulate appetite control by improving the sensitivity of the physiological satiety signalling system, by adjusting macronutrient preferences or food choices and by altering the hedonic response to food (Blundell et al., 2003). Indeed, dietary modification, associated with physical activity has been shown to exert significantly favorable effects on the treatment and prevention of stress-induced comorbidities, improving glycemia, blood pressure, body weight, fat distribution, and lipid profile, which in turn suggest that chronic degenerative diseases are largely preventable (Dagogo et al., 2010). Although exercise cannot change total cholesterol and LDL-cholesterol unless dietary fat intake is reduced, this result may be dependent on the amount of energy expenditure during exercise (Durstine et al., 2002). Furthermore, depending on the time that the exercise is performed (before or after ingestion of fatty foods), its acute responses related to improvement in lipoprotein metabolism may be different (Hashimoto et al., 2011). In a review of several studies realized by Leon & Sanchez

mobilized in response to the stressor toward oxidation rather than storage.

increased levels of brain testosterone (Mukai et al., 2006).

2001, one of proposals evaluated was the effects of aerobic exercise training on blood lipids and the relationship between these effects and diet. The results showed that majority of physically active individuals had an increase in HDL cholesterol, but this could be changed if there was a concomitant reduction in fat intake. The association between low-fat diet and exercise reduces LDL and HDL-cholesterol levels. Furthermore, reductions in total cholesterol, LDL-cholesterol and triglyceride levels were less frequently observed. As regards body weight loss, there was considerable variability between the groups, ranging from 7.2 Kg in the group that was not exposed to dietary intervention to 17.9 Kg in the group that underwent dietary intervention. In addition, Rubenfire et al., 2011, demonstrated that the association between changes in diet and exercise was effective in reducing cardiovascular risk in patients with metabolic syndrome. In this study, the nutritional component was based on a Mediterranean food pattern, and all the participants were provided with the information needed to optimize their nutritional choices in order to improve blood lipid and glucose levels, decrease body weight and blood pressure, and decrease insulin resistance (Rubenfire et al., 2011). It has also been proposed that high-fiber diets protect against obesity and cardiovascular disease by lowering insulin levels (Ludwig et al., 1999). In obese men, the implementation of a high-fiber and low-fat diet associated with regular physical activity resulted in significant reductions in inflammation and dyslipidemia by reducing serum lipids, insulin, oxidative stress, leukocyteendothelial interactions (Roberts & Barnard, 2005).

Dietary fat influences glucose and lipid metabolism by altering cell membrane function, enzyme activity, insulin signaling, and gene expression (Risérus et al., 2009; Yamazaki et al., 2011) and dietary fructose consumption appears to induce dyslipidemia, obesity (Stanhope et al., 2009) and hypertension (Cunha et al., 2007; Farah et al., 2006). A combination of social stress and high-fat diet resulted in a significant imbalance in lipid regulation associated with changes in the expression of hepatic genes, responsible for its regulation (Chuang et al., 2010). Therefore, clinical strategies based on low fat and sugar intake associated with increase in physical exercise have been used, and have contributed to reducing the risks of developing coronary and metabolic diseases.
