**2. Dyslipidemia induced by stress: Physiological mechanisms**

Many studies have shown the effect of stress on lipid metabolism. Stress associated with a major disaster, such as an earthquake or loss of job and income is associated with increased total cholesterol, LDL, and triglycerides in the bloodstream (Stoney, 2007). The perception of increased stress during a period of high workload is associated with elevated cholesterol in the bloodstream and ingestion of foods that increase cholesterol (McCann et al., 1990). Acute psychological stress in healthy men and women reduces the clearance rate of exogenous fat (Stoney et al., 2002). Chronic psychological stress increased the plasma cholesterol level in medical students (O'Donnell et al., 1987). In a more recent study, Yoo et al., 2011, showed high prevalence of hypercholesterolemia in stressed female law enforcement officers in comparison with the general female population. Moreover, elevated basal cortisol concentrations and lower circadian cortisol variability can induce dyslipidemia in patients with depressive and anxiety disorders (Venn et al., 2009; Vogelzangs et al., 2007). These patients presented hypercortisolism, increased serum levels of total cholesterol, LDL, and triglycerides and decreased serum levels of HDL (Venn et al., 2009).

In animal studies, it has been shown that electric shock stress increases plasma cholesterol concentrations (Berger et al., 1980), and unpredictable immobilization stress decreases HDL, increases blood LDL, and very-low-density lipoprotein (VLDL) concentrations in rats (Bryant et al., 1988). Chronic mild unpredictable stress increases triglycerides, total cholesterol, VLDL, and LDL concentrations in the bloodstream of stressed rats compared with control rats and this effect was observed 15 days after the stress protocol had ended (Neves et al., 2009).

The stressful modern lifestyle exerts a strong influence on lipid metabolism (Black, 2002) and may transform adaptative responses to pathophysiological changes. Acute increases in blood lipids are necessary for the individual to survive and adapt to the stressor. However prolonged changes in lipid metabolism induced by chronic stress can result in cardiovascular diseases such as atherosclerosis, coronary heart disease, and stroke (Brindley et al., 1993).

The negative effects of sustained stress-induced dyslipidemia are related to a bidirectional relationship between stress hormones and insulin. Catecholamines directly stimulate free fatty acid and glycerol secretion in the bloodstream from fat depots, a process that may result from increased blood flow through adipose tissue or from adipose-β2 adrenoceptor stimulation (Stoney, 2007). Stress-induced high glucocorticoid concentration exerts a permissive effect on these lipolytic actions of catecholamines (Brindley et al., 1993). Since insulin regulates triglyceride synthesis and hepatic VLDL production, insulin resistance results in unregulated triglyceride synthesis and VLDL production (Stoney, 2007) and

with the greatest demand during the stress reaction, and support the fight or flight reaction

During acute stress, there is a rapid and transient increase in blood concentrations of total cholesterol, low-density lipoprotein (LDL), apoprotein B, triglycerides, and free fatty acids (Stoney, 2007). This increase persists as along as the stressor is maintained (Black, 2002), and disappears in stress-free periods (Stoney et al., 1999). In chronic stress situations, it has been shown that dyslipidemia is maintained and may persist even after the stressor is no longer

Many studies have shown the effect of stress on lipid metabolism. Stress associated with a major disaster, such as an earthquake or loss of job and income is associated with increased total cholesterol, LDL, and triglycerides in the bloodstream (Stoney, 2007). The perception of increased stress during a period of high workload is associated with elevated cholesterol in the bloodstream and ingestion of foods that increase cholesterol (McCann et al., 1990). Acute psychological stress in healthy men and women reduces the clearance rate of exogenous fat (Stoney et al., 2002). Chronic psychological stress increased the plasma cholesterol level in medical students (O'Donnell et al., 1987). In a more recent study, Yoo et al., 2011, showed high prevalence of hypercholesterolemia in stressed female law enforcement officers in comparison with the general female population. Moreover, elevated basal cortisol concentrations and lower circadian cortisol variability can induce dyslipidemia in patients with depressive and anxiety disorders (Venn et al., 2009; Vogelzangs et al., 2007). These patients presented hypercortisolism, increased serum levels of total cholesterol, LDL, and

In animal studies, it has been shown that electric shock stress increases plasma cholesterol concentrations (Berger et al., 1980), and unpredictable immobilization stress decreases HDL, increases blood LDL, and very-low-density lipoprotein (VLDL) concentrations in rats (Bryant et al., 1988). Chronic mild unpredictable stress increases triglycerides, total cholesterol, VLDL, and LDL concentrations in the bloodstream of stressed rats compared with control rats and this effect was observed 15 days after the stress protocol had ended

The stressful modern lifestyle exerts a strong influence on lipid metabolism (Black, 2002) and may transform adaptative responses to pathophysiological changes. Acute increases in blood lipids are necessary for the individual to survive and adapt to the stressor. However prolonged changes in lipid metabolism induced by chronic stress can result in cardiovascular diseases such as atherosclerosis, coronary heart disease, and stroke (Brindley

The negative effects of sustained stress-induced dyslipidemia are related to a bidirectional relationship between stress hormones and insulin. Catecholamines directly stimulate free fatty acid and glycerol secretion in the bloodstream from fat depots, a process that may result from increased blood flow through adipose tissue or from adipose-β2 adrenoceptor stimulation (Stoney, 2007). Stress-induced high glucocorticoid concentration exerts a permissive effect on these lipolytic actions of catecholamines (Brindley et al., 1993). Since insulin regulates triglyceride synthesis and hepatic VLDL production, insulin resistance results in unregulated triglyceride synthesis and VLDL production (Stoney, 2007) and

**2. Dyslipidemia induced by stress: Physiological mechanisms** 

triglycerides and decreased serum levels of HDL (Venn et al., 2009).

to a stressor.

present (Neves et al., 2009).

(Neves et al., 2009).

et al., 1993).

triglycerides are secreted by the liver in large quantities within the VLDL particles (Black, 2003). Therefore both catecholamines and glucocorticoids antagonize the actions of insulin, contributing to insulin resistance (Kyrou & Tsigos, 2009; Lafontan & Langin, 2009).

Moreover, hyperinsulinemia acts centrally to stimulate sympathetic nervous system activity, resulting in increased secretion of catecholamines (Black, 2003), and the absence of satisfactory insulin action facilitates the actions of cortisol and glucagon, which in turn stimulate phosphatidate phosphohydrolase activity to synthesize hepatic triglyceride (Brindley et al., 1993).

The cortisol also induces apoprotein B (apo B) secretion from the liver in the proportion of one apo B molecule per VLDL particle (Brindley et al., 1993), consequently increasing the VLDL concentrations in the bloodstream. As each VLDL particle is metabolized to intermediate-density lipoprotein (IDL) or LDL, the action of the cortisol that stimulates apo B secretion also results in increased LDL particles in the blood. Furthermore, in the presence of stress-induced insulin resistance, high levels of glucocorticoids suppress the hepatic LDL receptors, which delay LDL clearance (Stoney, 2007).

Contributing to all these processes, it has been shown that perilipin, which coats the surface of lipid droplets to restrict lipase access to the triglyceride core within the droplet, may suffer phosphorylation and/or down-regulation by glucocorticoid action, thereby facilitating the lipolysis of triglycerides in fatty acids and glycerol (Xu et al., 2001). This sets off a vicious cycle, leading to more and more triglycerides being produced by the liver and secreted in VLDL particles, as a result of the stimulation of glucocorticoids and fatty acids.

In addition, norepinephrine and cortisol inhibit lipoprotein lipase activity, leading to diminished triglyceride clearance, decrease in HDL concentration, and increase in VLDL, IDL, and LDL concentrations in the bloodstream (Stoney, 2007). Norepinephrine also diminishes hepatic triglyceride lipase activity, which in turn promotes high concentrations of lipoproteins rich in triglycerides in the blood (Stoney, 2007).

In the context of stress-induced dyslipidemia, changes in food ingestion must also be considered. During acute stress, transient dyslipidemia and food intake inhibition are mediated by β-adrenergic activation and increased hypothalmic corticotrophin releasing hormone (CRH) levels which act as catabolic signals. On the other hand, chronic activation of the hypothalamic-pituitary-adrenal axis has been associated with overeating and obesity (Dallman et al., 2004; Nishitani & Sakakibara, 2006). Many studies have supported this relationship. Lemieux & Coe, 1995, related that approximately 50% of women with posttraumatic stress disorder as a result of childhood sexual abuse were overweight, and also showed high concentrations of norepinephrine, epinephrine, and dopamine in urine. Changes in sleep-wake cycles associated with stress, resulting in sleep loss, induce decreased leptin levels, increased ghrelin levels, and increased hunger and appetite (Pejovic et al., 2010; Spiegel et al., 2004). In addition, the parent's lifestyle can influence metabolism, and individuals exposed to maternal stress during intrauterine life can exhibit deregulation of body weight control mechanisms and blood lipid profile (De Moura, 2008). The relationship between excessive glucocorticoids and visceral fat accumulation has also been discussed by Björntorp & Rosmond, 1999.

Thus, the typical response to chronic stress is not by way of avoiding food but by increasing the intake of sugar- and fat-rich comfort foods, which make people feel better

Dyslipidemia Induced by Stress 371

HPA axis Sympathetic nervous system

**STRESSOR**

Central Nervous System

> Insulin resistance

**DYSLIPIDEMIA**

Fig. 1. Schematic representation of physiological mechanisms of dyslipidemia induced by stress. Hypothalamic-pituitary-adrenal axis (HPA), low-density lipoprotein (LDL), verylow-density lipoprotein (VLDL), free fatty acids (FFA), neuropeptide Y (NPY), tumor necrosis factor (TNF-α), interleukin 6 (IL-6). Solid arrows show stimulatory effects; dashed

Atherogenic dyslipidemia is a major underlying cause of the development of atherosclerosis, which is an inflammatory disease (Mullick et al., 2006; Sheril et al., 2009). Since the stress-induced atherogenic lipid profile potentiates the effects of dietary and genetic factors in atherogenesis (Brindley et al., 1993), stress has been recognized as a risk factor for atherosclerosis (Kyrou & Tsigos, 2009; Shively et al., 2009). However, despite the association between dyslipidemia and atherosclerosis, many individuals develop severe atherosclerotic lesions associated with low serum lipid concentration, and others develop far more severe atherosclerosis than would be expected on the basis of a modest elevation of serum lipids (Kaplan et al., 1983). In this context, other effects of stress, not related specifically to dyslipidemia, are also involved in atherogenesis (Bierhaus et al., 2003; Gu et al., 2009) and approximately 40% of cases without known causal factor, have been attributed

**3. Stress, dyslipidemia and atherosclerosis: Putative mechanisms** 

Catecholamines

Lipoprotein lipase

Abdominal obesity

NPY

Hyperinsulinemia

Comfort food ingestion

NPY

Peripheral effects via sympathetic nerves

Fat depots (lipolysis)

LEPTIN TNF-α IL-6

**LDL receptor**

arrows indicate inhibitory effects.

to stressful situations (Black, 2002).

LDL

FFA Glycerol

Liver

VLDL Triglycerides

Glucocorticoids

(Stoney, 2007; Torres & Nowson, 2007). Dallman et al., 2003, suggested that people or animals eat comfort food in an attempt to reduce activity in the 'chronic stress-response network' with its attendant anxiety. They suggested the following mechanism: first, in the periphery, glucocorticoids stimulate accretion of mesenteric energy stores; second, as the abdominal energy-generated (unidentified) signal increases, the negative input to catecholaminergic cells in the nucleus tractus solitarius reduces the synthesis of enzymes required for norepinephrine synthesis; third, the decreased noradrenergic signal to the hypothalamic paraventricular nucleus (PVN), in turn, decreases CRH synthesis and secretion. Thus, there is a powerful metabolic feedback control of CRH in the PVN, which may indirectly decrease glucocorticoid-action in the central nucleus of the amygdala; and thereby control anxiety (Korte et al., 2005). Consequently, all these mechanisms can lead to obesity and dyslipidemia due to overeating. In addition, it has been proposed that when chronic stress, to which animals and humans cannot easily adapt, is combined with high-fat high-sugar diets, it stimulates the sympathetic nerves to upregulate the expression of neuropeptide Y, an adrenergic cotransmitter and stress mediator. Stress and hypercaloric diets also increase glucocorticoid concentration in visceral fat, which in turn upregulates the expression of neuropeptide Y and its receptor Y2R, resulting in fat growth, hyperinsulinemia and hyperlipidemia (Bartolomucci et al., 2009; Kuo et al., 2008).

Some studies have also shown that glucocorticoid actions in the target tissues depend not only on circulating hormone levels, but also on intracellular glucocorticoid receptors and activities of both 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 2 (Bose et al., 2009). The effects of glucocorticoid are enhanced by the enzyme 11β-HSD1 in the stromal cells of visceral fat, since this enzyme catalyzes the conversion of inactive cortisone to active glucocorticoid in local tissue. It has been shown that transgenic knockout mice, which overexpress 11β-HSD1 in adipose tissue, present accumulation of visceral adipose tissue, hypertension, dyslipidemia and glucose intolerance (Masuzaki et al., 2001; Masuzaki & Flier, 2003). Therefore 11β-HSD1 plays an important role in the development of metabolic disease associated with stress (Bose et al., 2009; Walker & Stewart, 2003).

In addition, cytokines such as interleukin 6 (IL-6), tumor necrosis factor (TNF)-α, and leptin released from fatty cells also contribute to dyslipidemia induced by stress. IL-6 increases the activity of 11β-HSD1 with consequent expansion of visceral fat. TNF-α induces lipolysis in adipose tissue. Both IL-6 and TNF-α decrease lipoprotein lipase activity, contributing to the increase in triglyceride levels induced by stress (Black, 2003). Moreover, TNF-α induces insulin resistance because it depresses insulin receptor activity (Yudkin et al., 2000). TNF-α also induces IL-6 synthesis, and stimulates leptin synthesis, which acts centrally to decrease appetite and increase thermogenesis to decrease fat storage (Black, 2003). Leptin increases the activity of sympathetic nervous system centrally (Mohamed-Ali et al., 1998), which in turn stimulates increased release of TNF-α and IL-6 from adipocytes (Black, 2003). This sympathetic nervous system hyperactivity induced by high levels of leptin in the bloodstream would provide an additional effect of catecholamines on the genesis of insulin resistance and dyslipidemia associated with stress in obese individuals.

Therefore, dyslipidemia induced by stress involves complex interactions among stress hormones, insulin, adipose tissue metabolism and cytokines. Figure 1 indicates the physiological mechanisms of dyslipidemia induced by stress.

(Stoney, 2007; Torres & Nowson, 2007). Dallman et al., 2003, suggested that people or animals eat comfort food in an attempt to reduce activity in the 'chronic stress-response network' with its attendant anxiety. They suggested the following mechanism: first, in the periphery, glucocorticoids stimulate accretion of mesenteric energy stores; second, as the abdominal energy-generated (unidentified) signal increases, the negative input to catecholaminergic cells in the nucleus tractus solitarius reduces the synthesis of enzymes required for norepinephrine synthesis; third, the decreased noradrenergic signal to the hypothalamic paraventricular nucleus (PVN), in turn, decreases CRH synthesis and secretion. Thus, there is a powerful metabolic feedback control of CRH in the PVN, which may indirectly decrease glucocorticoid-action in the central nucleus of the amygdala; and thereby control anxiety (Korte et al., 2005). Consequently, all these mechanisms can lead to obesity and dyslipidemia due to overeating. In addition, it has been proposed that when chronic stress, to which animals and humans cannot easily adapt, is combined with high-fat high-sugar diets, it stimulates the sympathetic nerves to upregulate the expression of neuropeptide Y, an adrenergic cotransmitter and stress mediator. Stress and hypercaloric diets also increase glucocorticoid concentration in visceral fat, which in turn upregulates the expression of neuropeptide Y and its receptor Y2R, resulting in fat growth, hyperinsulinemia and hyperlipidemia (Bartolomucci et al., 2009; Kuo et al.,

Some studies have also shown that glucocorticoid actions in the target tissues depend not only on circulating hormone levels, but also on intracellular glucocorticoid receptors and activities of both 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 2 (Bose et al., 2009). The effects of glucocorticoid are enhanced by the enzyme 11β-HSD1 in the stromal cells of visceral fat, since this enzyme catalyzes the conversion of inactive cortisone to active glucocorticoid in local tissue. It has been shown that transgenic knockout mice, which overexpress 11β-HSD1 in adipose tissue, present accumulation of visceral adipose tissue, hypertension, dyslipidemia and glucose intolerance (Masuzaki et al., 2001; Masuzaki & Flier, 2003). Therefore 11β-HSD1 plays an important role in the development of metabolic

In addition, cytokines such as interleukin 6 (IL-6), tumor necrosis factor (TNF)-α, and leptin released from fatty cells also contribute to dyslipidemia induced by stress. IL-6 increases the activity of 11β-HSD1 with consequent expansion of visceral fat. TNF-α induces lipolysis in adipose tissue. Both IL-6 and TNF-α decrease lipoprotein lipase activity, contributing to the increase in triglyceride levels induced by stress (Black, 2003). Moreover, TNF-α induces insulin resistance because it depresses insulin receptor activity (Yudkin et al., 2000). TNF-α also induces IL-6 synthesis, and stimulates leptin synthesis, which acts centrally to decrease appetite and increase thermogenesis to decrease fat storage (Black, 2003). Leptin increases the activity of sympathetic nervous system centrally (Mohamed-Ali et al., 1998), which in turn stimulates increased release of TNF-α and IL-6 from adipocytes (Black, 2003). This sympathetic nervous system hyperactivity induced by high levels of leptin in the bloodstream would provide an additional effect of catecholamines on the genesis of insulin resistance and dyslipidemia associated with

Therefore, dyslipidemia induced by stress involves complex interactions among stress hormones, insulin, adipose tissue metabolism and cytokines. Figure 1 indicates the

disease associated with stress (Bose et al., 2009; Walker & Stewart, 2003).

physiological mechanisms of dyslipidemia induced by stress.

2008).

stress in obese individuals.

Fig. 1. Schematic representation of physiological mechanisms of dyslipidemia induced by stress. Hypothalamic-pituitary-adrenal axis (HPA), low-density lipoprotein (LDL), verylow-density lipoprotein (VLDL), free fatty acids (FFA), neuropeptide Y (NPY), tumor necrosis factor (TNF-α), interleukin 6 (IL-6). Solid arrows show stimulatory effects; dashed arrows indicate inhibitory effects.
