Autonomic dysregulation and the metabolic syndrome: pathologic partners in an emerging global pandemic

REVIEW ARTICLE

Autonomic dysregulation and the metabolic syndrome: pathologic partners in an emerging global pandemic

Heno Ferreira Lopes; Brent M. Egan

Unidade de Hipertensão do Instituto do Coração – FM-USP, Departments of Medicine & Pharmacology - Medical University of South Carolina - São Paulo, Brazil and Charleston, South Carolina, USA

^{Mailing Address}

This review will examine the importance of the autonomic nervous system both in the pathophysiology and complications of the metabolic syndrome. Metabolic syndrome refers to a constellation of risk factors related to insuline resistance and obesity with a pattern of central fat distribution. While the insulin resistance syndrome has been attracting attention over the last three decades, the metabolic syndrome achieved heightened prominence after the publication and review of the World Health Organization (WHO) Expert Committee Report on the diagnosis and classification of diabetes mellitus, in 1998, and the National Cholesterol Education Program guidelines (Adult Treatment Panel [ATP] III) in 2001, in the United states^1-3. Although definitions provided differ somewhat, both anticipate a significant increase in the risk of coronary heart disease and cardiovascular disease in general^4-6.

The metabolic syndrome affects a substantial proportion of adults in societies characterized by excessive calorie intake, use of labor-saving devices, and passive leisure activities. This syndrome is liable to become a pandemic, because obesity has been growing dramatically as the world's population ages⁷. Its costs, both in health and financial terms, are extremely high and can be more devastating than the largest armed conflict. This review focuses primarily on the role of the sympathetic nervous system in the metabolic syndrome, providing a gamut of information and directing its efforts rationally to prevent and treat the health consequences of this increasingly prevalent condition effectivelly.

Metabolic syndrome

Definition

The WHO and ATP-III definitions of the metabolic syndrome are not similar1-3 (Tab. 1).

Associated risk factors

This syndrome is associated with postprandial hyperinsulinemia, insulin resistance with reduced glucose and fatty acids, higher levels of denser LDL-cholesterol particles⁸, low HDL-cholesterol levels and smaller HDL-cholesterol particles. Obesity and the metabolic syndrome are related to high levels of inflammatory markers/factors, including interleukins, tumor necrosis factor-a (TNF-a), C-reactive protein⁹, and abnormal fibrinolysis, such as higher plasminogen activator inhibitor-1 (PAI-1) levels¹⁰and increased oxidative stress^11,12. Other evidence suggests that the metabolic syndrome is associated with microalbuminuria¹³, cardiovascular autonomic regulation abnormalities, and activation of one or more components of the renin-angiotensin system. Several factors contribute to the metabolic syndrome. The autonomic nervous system seems to play a key role in various aspects of the syndrome, including pathophysiology and complications¹⁴.

Prevalence: WHO definition

Criteria established by WHO for the metabolic syndrome were applied to eight different European cohorts, and its prevalence was determined for men and women from 40 to 55 years old and also for those older than 55². Prevalence according to age and gender is summarized in Table 2.

NCEP/ATP III definition

Metabolic syndrome age-adjusted prevalence based on data from the Unites States' Third National Health and Nutrition Examination Survey (NHANES III), covering 1988–1994, using ATP III criteria, was 23.7%, or approximately 47,000,000 adults¹⁵. Although ATP III did not use the body mass index (BMI, kg/m²) to define the metabolic syndrome, this condition is strongly related do BMI in men and women alike, as shown in Table 3¹⁶.

Future trends in prevalence

The metabolic syndrome has reached epidemic proportions and is likely to become endemic in the coming years, owing to rapid increase in obesity prevalence magnified by two strong demographic trends:

Obesity prevalence, trends and associated health risks. Obesity risks, including hypertension, diabetes, and increased cardiovascular and renal disease risks, have been described for more than 80 years¹⁷. Subsequent studies have shown that obesity, particularly central or abdominal obesity, is associated with hypertension, fast heart rate, hyperinsulinemia, and insulin resistance with abnormal carbohydrate and lipid metabolism^14,18,19. This syndrome is associated with premature cardiovascular morbidity and mortality, including sudden death^7,8. Despite the recent information explosion on risks associated with overweight, the overweight (BMI between 25-30 kg/m²) and obesity (BMI >30 kg/m²) epidemic remains expanding at an unpredictable rate.

Age-adjusted prevalence of obesity in the United States rose from 22.9% in the 1988-1994 survey to 30.5% in the 1999-2000 survey²⁰. Overweight prevalence rose from 55.9% to 64.5% between 1994 and 2000. A recent US survey suggests that obesity prevalence increased more in 2001 than in 2000²¹. This rapid increase in obesity rate has also been found in developing countries, such as Brazil. The presence of obesity in individuals with neither risk for nor cardiovascular disease is associated with an important increase in relative risk for cardiovascular disease in the subsequent decade, especially among men (Table 4)²². Epidemicobesity strikes young adults and children not only in developed countries, but also in emerging economies all over the world⁷. In fact, epidemic obesity is growing rapidly in these new targets (emerging countries).

Given the strong relationship between obesity, the metabolic syndrome (Table 2), and the development of cardiovascular risk factors and events over the next decade among overweight and obese adults with no risk disease or risk for it, the magnitude of the metabolic syndrome and its related health problems will reach catastrophic proportions.

Aging

Mean age of the population is rising rapidly throughout most of the world, whereas birth rate is decreasing. In the United States, while the number of adults age 60 or older was projected to reach 35 million between 2000 and 2022, the number of adults between 30 and 49 was projected to reduce by approximately two million²³. Metabolic syndrome prevalence is age-dependent. Among adult Americans in the age group between 20 and 29, around 7% meet ATP III criteria for the metabolic syndrome¹⁰. This prevalence rises to 40% or more among those who are 60 or older. Thus, between 2000 and 2022, the absolute number of adult Americans with the metabolic syndrome is likely to increase more than 12 million individuals due to increasing age alone.

Ethnic trends - Obesity, the major controller of the metabolic syndrome, occurs more often among Hispanics and Africans than among Caucasians in the United States. These demographic differences extend to children, and obesity and its associated health problems are nearly doubling the rate in these high-risk populations, compared with Caucasians^24,25. Considering the rapid growth of ethnic minorities in the United States, prevalence of the metabolic syndrome and its complications is likely to increase dramatically in the following years unless effective, culturally-appropriate, and population-based strategies are implemented to promote health.

Clinical significance - Impact on coronary artery disease (CAD), cardiovascular disease (CVD), and overall mortality. The clinical significance of the metabolic syndrome is not defined by its prevalence, but rather by its impact on health outcomes and costs. Metabolic syndrome, defined by WHO and ATP III in Table I, is associated with significantly higher mortality from CAD and CVD, as well as with overall mortality^5,6. When the WHO and ATP III criteria were applied to a Finnish male population followed up on from 1989 to 1998, an important positive relationship was found with mortality from CAD, CVD, and overall mortality (Table 5)⁵.

Economic impact

The cost of obesity alone in the United States was estimated in 46 to 68 billion dollars in 1990, rose to 99 billion dollars in 1995 and is likely to have exceeded this amount annually²⁶. While obesity hastens degenerative joint diseases and increases breast, uterus, prostate, and spine cancer rates²⁷, most of the high cost associated to obesity is generated by cardiovascular risk factors and events, that is, it is related to the metabolic syndrome.

Given prevalence, future trends, clinical impact, and economic burden of the metabolic syndrome, this disorder currently constitutes a major health problem and is still on the rise. Further efforts to identify the mechanisms and consequences involved in sympathetic dysfunction may provide insights into therapeutic advances to reduce cardiovascular risk and its consequences. Now, we are going to explore the literature relating sympathetic nervous system, obesity, and metabolic syndrome.

Overweight, obesity, plus insulin action and dynamics

Body mass index and insulin action and dynamics are interrelated¹. For example, among Italians, hyperinsulinemia and insulin resistance affect only ~10% of subjects with BMI < 25 kg/m², but 60% or more of subjects with BMI > 35 kg/m^{2 29}. In some ethnic groups, such as Asians and Afro-americans, the risk for insulin resistance and several features of the metabolic syndrome starts when the BMI is below 25 kg/m^{2 30,31}.

Although physicians and scientists have only recently recognized health hazards posed by obesity, its adverse impact has been known for at least 80 years⁷. The acknowledgement of obesity epidemics worldwide over the last decades has led to an explosion of scientific interest and discoveries. Insight gained from intensified investigations include from clinical epidemiology observations to experiments in the areas of cell and molecular biology. A similar range of scientific research has furthered our understanding of the role of the sympathetic nervous system in the metabolic syndrome, also called insulin resistance syndrome.

This review intends to summarize information from community to bedside and laboratory bench in order to shed new light on the underlying sympathetic activation involved in the pathogenesis of this condition, as well on metabolic and cardiovascular consequences among individuals with the insulin resistance syndrome. Evidence suggests that abnormalities in neurogenic regulation are partly directed to several aspects of the syndrome and that enhanced sympathetic tone may contribute to the dimension of the metabolic syndrome and the complications associated with target organs. Therefore, further understanding of the causes and consequences of sympathetic hyperactivity in the metabolic syndrome may intensify efforts to more effective prevention and better management of this condition and its complications. We will start this discussion by providing a brief, general overview of obesity and insulin resistance epidemiology.

Sympathetic function in obesity

Obesity is not a homogeneous disorder. Both in animals and humans, evidence of sympathetic hypofunction and hyperfunction has already been demonstrated³². Collectively, the available literature strongly suggests sympathetic hyperactivation in a substantial subgroup of subjects. Several studies provide clues to the pathogenesis and consequences of sympathetic hyperactivity in obesity (Fig. 1).

In a subgroup of obese subjects, sympathetic tone is found to be heightened in key organs, such as the kidney, skeletal muscle, and peripheral vessels^33-35. Evidence of increased sympathetic tone to the heart in humans is not as strong, especially in normotensive obese patients³³. Impaired autonomic control of heart rate variability, including decreased vagal tone, with or without increased sympathetic tone, is well documented^36,37. Sympathetic activation in many target sites seems to play an important role in the pathogenesis of insulin resistance related to obesity^38,39, hypertension^40-43, renin-angiotensin system activation^43-45, and sudden death³⁶. Now we will explore evidence from several animal and human studies documenting that sympathetic nervous system activity is activated in obesity and insulin resistance.

Evidence of sympathetic activation in obesity and insulin resistance Animal studies

Evidence of sympathetic hypofunction and hyperfunction has already been demonstrated in animal obesity models³². In fact, sympathetic hypofunction seems to be related to low metabolic rates, which contribute to obesity in rodents⁴⁶.In healthy animals, obesity induced by excessive intake of food is associated with sympathetic activation and hypertension^40,47. Sympathetic activation is prematurely induced by overeating and reverted with weight loss. Apparently, the onset of diet-induced sympathetic alterations both precedes and triggers changes in the renin-angiotensin system activity^40,43. In some of these models, hypertension is prevented or reverted either by central -2 receptor agonists or a combined -1 and -adrenergic blockade^40-42. Findings from experimental studies have provided information on the mechanisms whereby obesity and insulin resistance activate the sympathetic nervous system and thus contribute to cardiovascular disease risk. Results from these studies indicate that the relationship between obesity, insulin resistance, and sympathetic function is complex and appears to be modified by genetic and environmental factors⁴⁸.

In normotensive rats, a high-saccharose diet, even in the absence of weight gain, induces insulin resistance and hypertension, which is attenuated by centrally acting -2 adrenergic agonists⁴⁹. In rats and dogs, hypertension induced by high saccharose or fat diets is abolished by clonidine, whereas hyperinsulinemia is affected variably^40,49.

Human studies

Plasma and urinary catecholamines, systemic or regional norepinephrine turnover, and direct nerve recording (microneurography) are used to measure sympathetic activity in humans. All these methods have provided evidence for sympathetic hyperfunction among obese subjects with metabolic syndrome.

Plasma catecholamines – A number of studies identified higher plasma catecholamine levels in obese subjects, particularly those with high blood pressure⁵⁰. Moreover, weight loss is associated with a relatively rapid reduction in plasma norepinephrine, which is correlated to a drop in blood pressure that accompanies the negative balance of calories⁴³. Studies have demonstrated that plasma norepinephrine is elevated in obese children with high blood pressure, and that this is a predictor of the blood pressure drop that occurs with salt restriction⁵¹.

These data suggest that sympathetic hyperactivity contributes to sodium retention and increased blood pressure in obese children, which is consistent with evidence from studies on regional catecholamine turnover in obese adults³³.

Studies of regional norepinephrine kinetics - Esler et al, using regional norepinephrine kinetics, identified enhanced sympathetic activity in the heart and kidney of hypertensive patients^33,52. Sympathetic activation is thought to play an important role in the pathogenesis of hypertension in these individuals. Although the pathogenesis of sympathetic activation has not yet been fully elucidated, studies on hypertensive patients have identified increased brain norepinephrine turnover, which may explain the heightened cardiac and renal sympathetic tone⁵².

Using regional norepinephrine turnover, increased renal sympathetic activity was identified in obese normotensive and hypertensive patients³³. Since the kidney is critical for blood pressure control⁵³, sympathetic hyperactivity is difficult and complex to interpret in obese normotensive subjects. Obesity is associated with volume expansion, and renal sympathetic hyperactivity may participate in maintaining volume expansion in normotension conditions in the presence of the renal vasodilation experienced by the obese patient. If the sympathetic activity causes more sodium retention and volume expansion than can be balanced by the natriuretic effect of renal vasodilation, then higher blood pressure will be necessary to maintain the sodium-volume homeostasis, thus resulting in hypertension.

Based on studies using norepinephrine turnover, cardiac sympathetic tone does not seem to be elevated in normotensive obese subjects and is modestly elevated in hypertensive obese subjects³³. From these studies on norepinephrine kinetics, regional differences in sympathetic function emerge among obesity, hypertension, and the combination of both.

Muscle sympathetic nerve activity (MSNA) – Muscle sympathetic nerve activity is higher in obese normotensive and hypertensive subjects than in non-obese normotensive subjects⁵⁴. Grassi et al demonstrated that weight loss in obese normotensive subjects decreased MSNA and plasma norepinephrine, while it improved baroreflex stimulation and glucose uptake⁵⁵.

Changes in MSNA and glucose uptake may be related. In a study involving regional dynamics performed by Jamerson et al, an inverse relationship was found between alpha-adrenergic vascular tone and insulin-mediated cell glucose uptake³⁹. Hence, it is tempting to speculate that enhanced MSNA in normotensive obese subjects increases vasoconstriction and contributes to blunting insulin-mediated glucose transport. While vasoconstriction by any cause has been implicated in insulin resistance⁵⁶, the effect of alpha-adrenergic vasoconstriction in glucose uptake seems to be more adverse than angiotensin-induced vasoconstriction³⁹. However, the marked reduction in MSNA associated with weight loss in normotensive obese subjects might have reduced alpha-adrenergic vasoconstriction and improved insulin-mediated glucose uptake.

In obese subjects, discriminating the caloric restriction effect from the weight loss effect in MSNA presents a challenge. Apparently, not only is reduction in calorie intake necessary but also significant weight loss. After a three-day diet to make women hungry, MSNA remained unchanged. Nevertheless, measurements obtained byAndersson et al when women lost 7% of baseline weight showed significant reduction in this activity.

Muscle sympathetic nerve activity has been reported to be higher in men than in women. In studies focused on evaluating this gender-related difference, Jones et al examined the relationship between body fat and MSNA in men and women⁵⁸ and found that it was more strongly correlated with central fat than with peripheral fat. Central fat, or the male fat distribution pattern, is associated with a greater degree of hyperinsulinemia, insulin resistance, hypertension, diabetes, and coronary artery disease than peripheral fat, or the female fat distribution pattern^19,59. The marked sexual dimorphism in fat distribution is present in young adults and decreases as women gain weight and show a centripetal distribution of fat with age⁶⁰. Moreover, overweight is more strongly related to hypertension in men than in women older than 45⁶¹. These findings reported in the literature relating MSNA with obesity strengthen the possibility that enhanced sympathetic activation among subjects with abdominal obesity contributes to their tendency to hypertension, insulin resistance, and diabetes.

Obesity and hypertension have separate and additional effects in MSNA. In studies conducted by Grassi et al, MSNA was similarly elevated (around 40% to 50%) in lean hypertensive and obese normotensive subjects, compared to lean normotensive subjects⁵⁴. In obese hypertensive subjects, MSNA was almost twice as high as that of lean normotensive subjects, suggesting that obesity and hypertension in MSNA were approximately additive. These investigators showed that reflex modifications in MSNA secondary to blood pressure changes were impaired in obese normotensive subjects, compared to lean normotensive and lean hypertensive subjects. Baroreflex impairments mediated by MSNA changes were greater in obese hypertensive than in obese normotensive subjects. These findings indicate that obesity is associated with increased MSNA, as well as worse MSNA regulation by baroreceptors. These abnormalities related to MSNA in obese subjects are magnified in the presence of concomitant hypertension.

Spectral analysis – Obese patients are more likely to experience ventricular arrhythmias and sudden death than lean subjects⁶². It is noteworthy that changes in the sympathetic and parasympathetic control of heart rate are greater in women with visceral obesity than in those with lower-body obesity⁶². Furthermore, weight loss from caloric restriction improves parasympathetic tone to the heart at night and reduces heart sympathetic/parasympathetic tone ratio during the day without changing resting heart rate⁶³. Although this review focuses primarily on the sympathetic nervous system, obesity is associated with abnormalities in the parasympathetic function that may be clinically relevant. Many autonomic changes associated with obesity improve with weight loss.

Potential mechanisms that may contribute to sympathetic activation in obesity

Several factors involved in the sympathetic activation that occurs in obesity are mentioned in the literature. Since obesity is a heterogeneouos condition, relative contribution of these factors may vary depending on changes in other biological, genetic, and environmental factors. Now we are going to analyze the evidence for several factors that can increase sympathetic activity in obesity. The following list is not meant to be exclusive, and there may be other factors.

Insulin – Extensive literature on animals and humans indicates that elevated plasma insulin levels, even within the physiological range, activate the sympathetic nervous system. In fact, theories linking hyperinsulinemia and insulin resistance with hypertension are based on the assumption that potential pressor effects of insulin are maintained (e.g. sympathetic activation and renal sodium retention), while some potential depressor effects are reduced (e.g. vasodilation), an argument that is beyond the scope of this review.

A series of experiments conducted by Anderson et al at the University of Iowa has shown that euglycemic hyperinsulinemia increases the MSNA in healthy young and elderly subjects, as well as in subjects with borderline hypertension^64,65. In spite of differences in terms of insulin action and peripheral vasodilation, no short-term increase in blood pressure occurs in these groups. In other studies, the MSNA is more strongly correlated with BMI (n = 37, r = 0.67, p < 0.001) and total body fat (r = 0.64, p < 0.001) and less strongly correlated with plasma insulin (r = 0.34, p < 0.04)⁶⁶. These data suggest that hyperinsulinemia may account solely for a small part of the sympathetic activation found in obesity. However, contrary to reports from other investigators, this group observed that obese subjects are resistant to insulin's action to increase MSNA, but are equally responsive to other stimuli that increase MSNA. Collectively, evidence suggests that insulin contributes to, yet may not fully explain, the sympathetic activation that occurs in obesity.

Leptin – Many studies have documented that leptin induces sympathetic activation both in animals and humans. Leptin, like insulin, has actions that are potentially pressor and others that are depressor⁴⁸. For example, leptin acts directly on the kidney by increasing renal sodium excretion and nitric oxide production, which may result in a drop in blood pressure. Leptin also increases sympathetic tone in the heart, kidneys, and adrenals, which may raises blood pressure. While short-term infusion of leptin in animals usually does not raise blood pressure, long-term leptin infusion has a pressor effect. Short-term leptin infusions are natriuretic, whereas long-term infusions reduce renal blood flow, thus enhancing sodium retention, and increase renal vascular resistance. Other evidence also implicates leptin in some models of hypertension associated with obesity. Although both insulin and leptin may activate the sympathetic nervous system, regional patterns of sympathetic activation differ with these peptides. Additionally, in humans, the multivariate analysis shows that MSNA seems to be more related to plasma leptin than to insulin⁶⁷.

Non-esterified fatty acids (NEFAs) – Non-esterified fatty acids or free fatty acids are usually elevated in metabolic syndrome subjects and are less responsive to suppression by insulin^68,69. Elevated plasma fatty acids are strongly correlated to abnormalities in the glucose and lipid metabolism that follows insulin resistance^70,71. Until the last decade, abnormalities in NEFAs metabolism were not related to sympathetic activation and cardiovascular regulation.

In minipigs, an increase in NEFA plasma levels through infusion of Intralipip, a source of triglyceride, and heparin, which activates lipoprotein lipase and accelerates hydrolysis of fatty acids from triglyceride, induces vasoconstriction and raises blood pressure⁷². In normotensive rats, the portal venous infusion of oleate solution induces sympathetic activation and raises blood pressure. The pressor response induced by oleate is blocked by a-1-adrenoceptor antagonists⁷³. In dogs, oleate infusion failed to induce sympathetic activation or pressor response⁷⁴. In humans, the two-fold increase in non-esterified fatty acids during Intralipid and heparin infusion raised blood pressure in ~12-14/6–8 mmHg in a four-hour period⁷⁵. Despite blood pressure elevation, heart rate increased ~8 bpm, consisting in neurogenic activation. In other study, Intralipid and heparin infusion also impaired endothelium-dependent vasodilation and enhanced a-1 adrenoceptor-mediated pressor reactivity^76,77. These two effects may be linked, because nitric oxide appears to attenuate a-adrenergic receptor-mediated vasoconstriction⁷⁸. One or more NEFA effects may explain their independent association as predictors of hypertension in the Paris Prospective Study⁷⁹.

Raising plasma fatty acids in humans also reduces baroreflex sensitivity⁸⁰; however, sympathetic control improves and parasympathetic control of heart rate variability decreases⁸¹. Since lower heart rate variability is associated with higher mortality rate, these findings may provide a potential mechanism linking higher fatty acid levels with sudden death in the Paris Prospective Study⁸².

Cytokines – The relationship between cytokines and sympathetic activation in obesity is speculative. Nevertheless, adipocytes produce a variety of inflammatory cytokines in proportion to their volume (Fig. 2). Obesity is associated with an increase in several of these pro-inflammatory peptides⁸³. Patients with heart failure or sleep apnea have increased cytokine levels and sympathetic activity, implying an association but not necessarily a causal relationship^84,85

Triiodothyronine – The active T3/reverse T3 ratio is associated with calorie intake, especially carbohydrate. This ratio increases rapidly with overeating and drops with fasting⁸⁶. Similarly, overeating is associated with increased deprivation of calories and decreased sympathetic activity, as described previously. Although this association increases the possibility of a causal relationship, some evidence links excess thyroid hormone (T4) levels with sympathetic activation while other evidence suggests sympathetic inhibition with hyperthyroidism. Further studies are needed to determine whether T4 and T3 effects on autonomic function are similar.

Eicosanoids – Adipose tissue secretes several peptides and other molecules that may be augmented among obese individuals⁸⁷. Eicosanoid products modulate autonomic activity⁸⁸ in a clinically significant manner⁸⁹. Therefore, abnormal eicosanoid metabolism in obesity may potentially impair sympathetic activation and inhibition⁸⁷.

Nitric oxide – Nitric oxide is a neurotransmitter and a local autocoid that modulates central sympathetic activity and peripheral neurogenic vasoconstriction^90,91. Leptin increases nitric oxide and sympathetic tone⁴⁸. Nitric oxide inhibition during exogenous leptin infusion enhances sympathetic tone significatly, especially to the heart⁹².

Endorphins – Endorphins act centrally as modulators of the sympathetic nervous system, appetite, and glucocorticoid function (hypothalamic-pituitary-adrenal axis)^93-95. In fact, endorphins seem to mediate the sympatholitic effects of a-2 and imidazoline receptor agonists⁹⁶. In short-term human studies, opioid antagonists are potent modulators of sympathetic activity⁹⁷. The endorphin/opioid effects on sympathetic function are not consistent and may depend on specific sites of action and on the subtype of activated receptor⁹⁸. Albeit speculative, abnormalities in endorphins may contribute to changes in energy intake relative to expenditure, both in the hypothalamic-pituitary-adrenal axis and autonomic functions described in obesity.

Neuropeptide Y – Neuropeptide Y (NPY) acts on the hypothalamus reducing the appetite and sympathetic flow, while improving sympathetic function peripherally⁹⁹. As with endorphins, there are several subtypes of NPY receptors to mediate specific effects on tissues. While NPY levels seem to be normal in obesity, changes in central and/or peripheral levels, as well as central NPY actions, may also contribute to impaired autonomic drive and tone.

Sleep apnea – Sleep apnea, unlike the aforementioned factors that may participate in neurogenic activation in obesity, is a medical condition rather than a peptide or lipid signaling molecule. It is a common yet underrecognized condition associated with obesity that might be present in about 50% of the hypertensive patients^85,100. Sleep apnea is associated with multiple changes, including insulin resistance, hyperleptinemia, hypercytokinemia, and sympathetic activation¹⁰¹. Several factors already discussed may contribute to adrenergic activation in patients with this condition. Furthermore, hypoxemia through activation of peripheral chemoreceptors and/or central effectors, for example, C1 and catecholamine-containing neurons in the medulla, may play the primary role in the sympathetic activation that occurs in sleep apnea¹⁰². It must be emphasized that imidazolines, including clonidine, inhibit sympathetic activation by acting on C1 neurons¹⁰³. Thus, activation of these receptors by hypoxia may potentially contribute to neurogenic hypertension in obese patients with sleep apnea.

Conclusion

Obesity has emerged as a worldwide epidemic, and health problems related to the metabolic syndrome have accompanied it. It is no exaggeration at all to say that this global epidemic is likely to become a pandemic in coming years. The clinical significance of the metabolic syndrome is highlighted by an association with a two- to four-fold increase in coronary heart disease, general cardiovascular diseases, and global mortality. The rapid increase in obesity prevalence, along with an aging population and increased proportion of high-risk ethnic groups, make it more important to implement effective strategies for primary prevention of the metabolic syndrome. Obesity is associated with several health risks that may have structural and functional impact on the body as a whole. Obesity is a heterogeneous condition modulated by a variety of genetic, environmental and developmental factors. Literature indicates that the sympathetic nervous system is activated in a substantial subgroup of subjects and seems to play a key role in insulin resistance, hypertension, tachycardia, complications in target organs, and sudden death which occur prematurely and more often in obese patients. Evidence implicates leptin and hyperinsulinemia in the sympathetic activation related to obesity. Hypothetically, other factors, such as fatty acids, neuropeptide Y, eicosanoids, and endorphins may participate in this sympathetic activation. It is speculated that cytokines and triiodothyronine can activate or cause the development of sympathetic activation in obesity. Sleep apnea, a frequent yet unrecognized complication of obesity, may trigger enhanced sympathetic activity through several mechanisms. Although not discussed in this review, behavioral factors, such as suppressed anger and hostility, might potentially contribute to autonomic changes in obese subjects¹⁰⁴.

This review focused on examining sympathetic activation causes and consequences in the metabolic syndrome. Hopefully, it contributes to a better understanding of those factors that induce sympathetic activation and its health consequences in subjects with insulin resistance. Scientific discoveries and understanding are critical to the development of new therapeutic interventions to reduce, at least in part, the devastating consequences of the metabolic syndrome both in health and economic terms, and current evidence indicates several promising research fields.

References

23. US Bureau of the Census and Money Magazine projections.

Received on 09/05/05

Accepted on 09/09/05

• 1. Alberti KGMM, Zimmet PZ: Diagnosis and classification of diabetes mellitus: Part 1 - provisional report of a WHO consultation. Diabetes Med. 1998; 15: 539-53.
• 2. The European Group for the Study of Insulin Resistance (EGIR): Frequency of the WHO metabolic syndrome in European cohorts, and an alternative definition of an insulin resistance syndrome. Diabetes Metab. 2002; 28: 364-76.
• 3. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486-97.
• 4. Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA. Metabolic syndrome and development of diabetes mellitus: Application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol. 2002; 156: 1070-7.
• 5. Lakka H-M, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002; 288: 2790-6.
• 6. Wilson PWF, D'Agostino RB, Parise H, Meigs JB. The metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Diabetes. 2002; 51 (suppl 2): A242.
• ⁷
  Obesity: Preventing and managing the global epidemic: Report of a WHO Consultation on Obesity, Geneva, 3 – 5 June 1997. World Health Organization, 1998.
• 8. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995; 75: 473-86.
• 9. Esposito K, Pontillo A, Di Pala C, Giugliano G, Masella M, Marfella R, Giugliano D. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: A randomized trial. JAMA. 2003; 289: 1799-804.
• 10. Bastard JP, Pieroni L, Hainque B. Relationship between plasma plasminogen activator inhibitor-1 and insulin resistance. Diab Metab Res Rev. 2000; 16: 192-201.
• 11. Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 1999; 85: 753-66.
• 12. Facchini FS, Hua NW, Reaven GM, Stoohs RA. Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? Free Rad Biol Med. 2000; 29: 1302-6.
• 13. Rowley K, O'Dea K, Best JD. Association of albuminuria and the metabolic syndrome. Curr Diab Rep. 2003; 3: 80-6.
• 14. Egan BM. Insulin resistance and the sympathetic nervous system. Curr Hypertens Rep. 2003; 5: 247-54.
• 15. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: Findings from the third National Health and Nutrition Examination Survey. JAMA. 2002; 287: 356-9.
• 16. Park Y-W, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Hemsfield SB. The Metabolic Syndrome: Prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988 1994. Arch Intern Med. 2003; 163: 427-36.
• 17. Prebble WE: Obesity: Observations on one thousand cases. Boston Med Surg J. 1923; 88: 617-21.
• 18. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995; 75: 473-86.
• 19. Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiol Rev. 1994; 74: 761-811.
• 20. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999 2000. JAMA. 2002; 288: 1723-7.
• 21. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003; 289: 76-9.
• 22. Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, et al. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med. 2001; 161: 1581-6.
• 24. Strauss RS, Pollack HA. Epidemic increase in childhood overweight, 19861998. JAMA. 2001; 286: 2845-8.
• 25. Gidding SS, Falkner B. Are we losing the game? Cardiovascular health in minority children. Ethnic Dis. 2002; 12: 171-3.
• 26. Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the United States. Obesity Research. 1998; 6: 97-106.
• 27. Garfinkel L. Overweight and cancer. Ann Int Med. 1985; 103 (6[part 2]): 1034-6.
• 28. Quesenberry CP, Caan B, Jacobson A. Obesity, health services use, and health care costs among members of a health maintenance organization. Arch Int Med. 1998; 158: 466-72.
• 29. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. J Clin Invest. 1997; 100: 1166-73.
• 30. Bunker CH, Ukoli FA, Matthews KA, Kriska AM, Huston SL, Kuller LH. Weight threshold and blood pressure in a lean black population. Hypertension. 1995; 26: 616-23.
• 31. Bnerji MA, Faridi, N, Atluri R, Chaiken RL, Lebovitz HE. Body composition, visceral fat, leptin, and insulin resistance in Asian Indian men. J Clin Endocrinol Metab. 1999; 84: 137-44.
• 32. Snitker S, Macdonald I, Ravussin E, Astrup A. The sympathetic nervous system and obesity: Role in aetiology and treatment. Obesity Rev. 2000; 1: 5-15.
• 33. Esler M, Magdalena R, Wiesner G, Kaye D, Hasting J, Lambert G. Sympathetic nervous system and insulin resistance: From obesity to diabetes. Am J Hypertens. 2001; 14: 304S309S.
• 34. Grassi G, Seravalle G, Dell-Oro R, Turri C, Bolla GB, Mancia G. Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension. 2000; 36: 538-42.
• 35. Egan B, Panis R, Hinderliter A, Schork N, Julius S. Mechanism of increased a-adrenergic vasoconstriction in human essential hypertension. J Clin Invest. 1987; 80: 812-17.
• 36. Quillot D, Fluckiger L, Zannad F, Drouin P, Ziegler O. Impaired autonomic control of heart rate and blood pressure in obesity: role of age and of insulin-resistance. Clin Autonomic Res. 2001; 11: 79-86.
• 37. Gao YY, Lovejoy, Spart An, Gray GA, Keys LK, Partington C. Autonomic activity assessed by heart rate spectral analysis varies with fat distribution in obese women. Obesity Res. 1996; 4: 55-63.
• 38. Pollare T, Lithell H, Selinus I, Berne C. Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia. 1988; 31: 415-20.
• 39. Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brant DO. Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension. 1993; 21: 618-23.
• 40. Rocchini AP, Mao HZ, Babu K, Marker P, Rocchini AJ. Clonidine prevents insulin resistance and hypertension in obese dogs. Hypertension. 1999; 33 [part 2]: 548-53.
• 41. Hall JE, Brands MW, Hildebrandt DA, Kuo J, Fitzgerald S: Role of sympathetic nervous system and neuropeptides in obesity hypertenson. Braz J Med Biol Res. 2000; 33: 605-18.
• 42. Wofford MR, Anderson DC, Brown CA, Jones DW, Miller ME, Hall JE. Antihypertensive -effect of a- and b-adrenergic blockade in obese and lean hypertensive subjects. Am J Hypertens. 2001; 14: 694-8.
• 43. Sower JR, Nyby M, Stern N, Beck F, Baron S, Catania R, et al. Blood pressure and hormone changes associated with weight reduction in the obese. Hypertension. 1982; 4: 686-91.
• 44. Esler M, Zweifler A, Randall O, Julius S, DeQuattro V. The determinants of plasma-renin activity in essential hypertension. Ann Int Med. 1978; 88: 746-52.
• 45. Egan BM, Stepniakowski K, Goodfriend TL. Renin and aldosterone are higher and the hyperinsulinemic effects of salt restriction greater in subjects with risk factor clustering. Am J Hypertens. 1994; 7: 886-93.
• 46. Rothwell NJ. Central regulation of thermogenesis. Crit Rev Neurobiol. 1994; 8: 1-10.
• 47. Carroll JF, Hunag M, Hester RL, Cockrell K, Mizelle HL. Hemodynamic alterations in hypertensive obese rabbits.Hypertension. 1995; 26: 465-70.
• 48. Mark AL, Correia M, Morgan DA, Shaffer RA, Haynes WG. State-of-the-art lecture: Obesity-induced hypertension: New concepts from the emerging biology of obesity. Hypertension. 1999; 33 [part 2]: 537-41.
• 49. Hwang I-S, Ho H, Hoffman BB, Reaven GM. Fructose-induced insulin resistance and hypertension in rats. Hypertension. 1987; 10: 512-16.
• 50. Tuck ML. Obesity, the sympathetic nervous system, and essential hypertension. Hypertension. 1992; 19 [suppl 1]: I67I77.
• 51. Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Kath V, et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Méd. 1989; 321: 580-85.
• 52. Esler M, Ferrier C, Lambert G, Eisenhofer G, Cox H, Jennings G. Biochemical evidence of sympathetic hyperactivity in human hypertension. Hypertension. 1991; 17 [suppl III]: III29-III35.
• 53. Guyton AC: Blood pressure control-special role of the kidneys and body fluids. Science. 1991; 252: 1813-16.
• 54. Grassi G, Seravalle G, Dell'Oro R, Turri C, Bolla GB, Mancia G. Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension. 2000; 36: 538-42.
• 55. Grassi G, Seravalle G, Colombo M, Bolla G, Cattaneo BM, Cavagnini F, et al. Body weight reduction, sympathetic nerve activity, and arterial baroreflex in obese normotensive humans. Circulation. 1998; 97: 2037-42.
• 56. Laakso M, Edelman SV, Brechtel G, Baron AD: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. J Clin Invest. 1990; 85: 1844-52.
• 57. Andersson B, Elam M, Wallin BG, Björntorp P, Andersson OK. Effect of energy-restricted diet on sympathetic muscle nerve activity in obese women. Hypertension. 1991; 18: 783-9.
• 58. Jones PP, Snitker S, Skinner JS, Ravussin E. Gender differences in muscle sympathetic nerve activity: Effect of body fat distribution. Am J Physiol. 1996; 270: E363E366.
• 59. Stern M, Haffner S. Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis. 1986; 6: 123-9.
• 60. Heitmann BL. Body fat distribution in the adult Danish population aged 35 65 years: An epidemiological study. Internat J Obes. 1991; 58: 535-45.
• 61. MacMahon SW, Blacket RB, Macdonald GJ, Hall W. Obesity, alcohol consumption and blood pressure in Australian men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study. J Hypertens. 1984; 2: 85-91.
• 62. Emdin M, Gastaldelli A, Muscelli E, Macerata A, Natali A, Camastra S, et al. Hyperinsulinemia and autonomic nervous system dysfunction in obesity: Effects of weight loss. Circulation. 2001; 103: 513-19.
• 63. Hirsch J, Leibel RL, Mackintosh R, Aguirre A. Heart rate variability as a measure of autonomic function during weight change in humans. Am J Physiol. 1991; 261: R1418-R1423.
• 64. Hausberg M, Hoffman RP, Somers VK, Sinkey CA, Mark AL, Anderson EA. Contrasting autonomic and hemodynamic effects of insulin in health elderly versus young subjects. Hypertension. 1997; 29: 700-5.
• 65. Anderson EA, Balon TW, Hoffman RP, Sinkey CA, Mark AL. Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension. 1992; 19: 621-7.
• 66. Wollenweider P, Tappy L, Randin D, Schneiter P, Jéquier E, Nicod P, et al. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest. 1993; 92: 147-54.
• 67. Monroe MB, Van Pelt RE, Schiller BC, Seals DR, Jones PP. Relation of leptin and insulin to adiposity-associated elevations in sympathetic activity with age in humans. Internat J Obes. 2000; 24: 1183-7.
• 68. Jensen MD, Haymond MW, Rizza RA, Cryer PE, Miles JM. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest. 1989; 83: 1168-73.
• 69. Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YDI. Measurement of plasma glucose, free fatty acids, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes. 1988; 37: 1020-4.
• 70. Ferrannini E, Barrett EJ, Bevilacqua S. Effects of fatty acids on glucose production and utilization in man. J Clin Invest. 1983; 72: 1737-47.
• 71. Cabezas MC, deBruin TWA, deValk HW, Shoulders CC, Jansen H, Erkelens DW. Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating apolipoprotein B overproduction and insulin resistance. J Clin Invest. 1993; 92: 160-8.
• 72. Bülow J, Madsen J, Hojgaard L. Reversibility of the effects on local circulation of high lipid concentrations in blood. Scan J Clin Lab Invest. 1990; 50: 291-6.
• 73. Grekin RJ, Dumont CJ, Vollmer AP, Watts SW, Webb RC. Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Am J Physiol. 1997; 273: R324-R330.
• 74. Hildebrandt DA, Kirk D, Hall JE. Renal and cardiovascular responses to chronic increases in cerebrovascular free fatty acids. Fed Proc. 1999; 13: 780 (abstract and personal communication).
• 75. Stojiljkovic MP, Zhang D, Lopes HF, Lee CG, Goodfriend TL, Egan BM. Hemodynamic effects of lipids in humans. Am J Physiol. 2001; R280: 1674-9.
• 76. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997; 100: 1230-9.
• 77. Haastrup T, Stepniakowski KT, Goodfriend TL, Egan BM. Lipids enhance a1-adrenergic receptor mediated pressor reactivity. Hypertension. 1998; 32: 693-8.
• 78. Thomas GD, Sander M, Lau KS, Huang PL, Stull JT, Victor RG. Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc Natl Acad Sci. 1998; 95: 15090-5.
• 79. Fagot-Campagna A, Balkau B, Simon D, Warnet J-M, Claude J-R, Ducimetière P, et al. High free fatty acid concentration: An independent risk factor for hypertension in the Paris Prospective Study. Internat J Epidemiol. 1998; 27: 808-13.
• 80. Gadegbeku CA, Dhandayuthapani A, Sadler JE, Egan BM. Raising lipids acutely reduces baroreflex sensitivity. Am J Hypertension. 2002; 15: 479-85.
• 81. Paolisso G, Manzella D, Rosaria MR, Ragno E, Barbieri M, Varricchio G, et al. Elevated plasma fatty acid concentrations stimulate the cardiac autonomic nervous system in healthy subjects. Am J Clin Nutr. 2000; 72: 723-30.
• 82. Jouven X, Charles M-A, Desnos M, Ducimetière P. Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation. 2001; 104: 756-61.
• 83. Chan JC, Cheung JC, Stehouwer CD, Emeis JJ, Tong PC, Ko GT, et al. The central roles of obesity-associated dyslipidaemia, endothlelial activation and cytokines in the Metabolic Syndrome-an analysis by structural equation modeling. Internat J Obes. 2002; 26: 994-1008.
• 84. Maguri SR, Hauser R, Schwartz J, Williams PL, Smith TJ, Christiani DC. Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation. 2001; 104: 986-91.
• 85. Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000; 85: 1151-8.
• 86. O'Dea K, Esler M, Leonard P, Stockigt JR, Nestel P. Noradrenaline turnover during under- and over-eating in normal weight subjects. Metabolism. 1982; 31: 896-9.
• 87. Engeli S, Sharma AM. Role of adipose tissue for cardiovascular-renal regulation in health and disease. Hormone Metab Res. 2000; 21: 485-99.
• 88. Brody MJ, Kadowitz PJ. Prostaglandins as modulators of autonomic nervous system. Fed Proc. 1974; 33: 48-60.
• 89. Stjärne L. Enhancement by indomethacin of cold-induced hypersecretion of noradrenaline in the rat in vivo by suppression of PGE mediated feedback control? Acta Physiol Scand. 1972; 86: 388-97.
• 90. Qadri F, Carretero OA, Scicli AG. Centrally produced nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and hypertensive spontaneously hypertensive rats. Jap J Pharmacol. 1999; 81: 279-85.
• 91. Tanioka H, Nakamura K, Fujimura S, Yoshida M, Suzuki-Kusaba M, Hisa H, et al. Facilitatory role of NO in neural norepinephrine release in the rat kidney. Am J Physiol. 2002; 282: R1436-R1442.
• 92. Kuo JJ, Jones OB, Hall JE. Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension. 2001; 37 [part 2]: 670-6.
• 93. Konishi S, Tsunoo A, Otsuka M. Enkephalins presynaptically inhibit cholinergic transmission in sympathetic ganglia. Nature. 1979; 282: 515-16.
• 94. Paquali R, Cantobelli S, Casimirri F, Boroluzzi L, Boschi S, Capelli M, et al. The role of opioid peptides in the development of hyperinsulinemia in obese women with abdominal fat distribution. Metabolism. 1992; 41: 763-7.
• 95. McCubbin JA, Survit RS, Williams RB, Nemeroff CB, McNeilly M. Altered pituitary hormone response to naloxone in hypertension development. Hypertension. 1989; 14: 636-44.
• 96. Ramirez-Gonzalez MD, Tchakarov L, Garcia RM, Kunos G. b-endorphin acting on the brainstem is involved in the antihypertensive action of clonidine and a-methyldopa in rats. Circ Res. 1983; 53: 150-7.
• 97. Bouloux P-M, Grossman A, Al-Damluji S, Bailey T, Besser M. Enhancement of the sympathoadrenal response to the cold-pressor test by naloxone in man. Clin Sci. 1985; 69: 365-8.
• 98. Rothman RB, Xu H, Char GU, Kim A, De Costa BR, Rice KC, et al. Phenylpiperidine opioid antagonists that promote weight loss in rats have high affinity for the k2B (enkephalin-sensitive) binding site. Peptides. 1993; 14: 17-20.
• 99. Balasubramaniam A. Clinical potential of neuropeptide Y family of hormones. Am J Surg. 2002; 183: 430-4.
• 100. Silverberg DS, Oksenberg A. Are sleep-related breathing disorders important contributing factors to the production of essential hypertension? Current Hypertension Reports. 2001; 3: 209-15.
• 101. Roux F, D'Ambrosio C, Mohsenin V. Sleep-related breathing disorders and cardiovascular disease. Am J Med. 2000; 108: 396-402.
• 102. Fletcher EC, Lesske J, Behm R, Miller CC 3rd, Stauss H, Unger T. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol. 1992; 1978-84.
• 103. Ries DJ, Morrison S, Ruggiero DA. The C1 area of the brainstem in tonic and reflex control of blood pressure: State of the art lecture. Hypertension. 1988; 11 [Suppl 1]: I8I13.
• 104. Johnson EH. Interrelationships between psychological factors, overweight, and blood pressure in adolescents. J Adolesc Health Care. 1990; 11: 310-18.

Publication Dates

• Publication in this collection
  21 Nov 2006
• Date of issue
  Oct 2006

History

• Accepted
  08 Sept 2005
• Received
  05 Sept 2005