Excess food intake and physical inactivity underlie the growing worldwide epidemic of obesity. Hyperglycemia, hyperlipidemia, and hypertension are common in obese individuals 89. Visceral obesity has been suggested to play a fundamental role in the simultaneous development of these disorders 10. Recent studies have demonstrated that adipose tissue is a major endocrine organ that secrets a variety of bioactive substances, termed adipocytokines. Adipocytokines secretion are altered as obesity develops, which may induce the metabolic disorders. As shown in Figure 1, accumulated visceral adipose tissue produce and secrete a number of adipocytokines, such as leptin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), angiotensinogen, and non-esterified fatty acids (NEFA), which induce development of hypertension 11. Visceral obesity is the main cause of the metabolic syndrome, and is associated with development of hypertension in the metabolic syndrome via a variety of pathways (Figure 1).

Insulin resistance is the main pathophysiologic feature of the metabolic syndrome. Several mechanisms connect insulin resistance with hypertension in the metabolic syndrome. An anti-natriuretic effect of insulin has been established by accumulating data indicating that insulin stimulates renal sodium re-absorption 121314. This anti-natriuretic effect is preserved, and may be increased in individuals with insulin resistance, and this effect may play an important role for development of hypertension in the metabolic syndrome 15. Strazzullo P, et al. investigated the relationship between the metabolic syndrome and renal tubular sodium handling 16. In their study, proximal fractional sodium re-absorption (FPRNa) was significantly greater in individuals with the metabolic syndrome, as compared with those without the metabolic syndrome 16. Further, in untreated obese individuals, age-adjusted FPRNa was significantly greater in individuals with insulin resistance as compared with those without insulin resistance 16. Insulin resistance is also associated with development of salt-sensitive hypertension through the anti-natriuretic effect of insulin 17.

In vitro studies have shown that insulin stimulates both endothelin-1 production and its action on the vascular wall 18. In vivo study has also demonstrated that high serum insulin level is associated with an increase in circulating endothelin-1 in healthy and insulin-resistant individuals 18. Endothelin-1 receptor antagonism effectively reduced blood pressure in animal models of insulin resistance and hypertension 18, suggesting a significance of endothelin-1 in the pathogenesis of hypertension in insulin resistance.

Serum catecholamine concentrations and muscle sympathetic nervous activity (MSNA) were significantly increased in obese individuals as compared with lean individuals 19, and MSNA in subjects with central obesity were significantly greater than those in individuals with peripheral obesity 19. Elevated resting heat rates 2021, and baroreflex dysfunction have been reported to play an important role in development of hypertension in the metabolic syndrome 22. Individuals with obstructive sleep apnea (OSA) have a high prevalence of the metabolic syndrome 2324, and OSA has been reported to be associated with sympathetic overactivity. Obese individuals exhibit an activated renin-angiotensin system 25, which induces hypertension. The renin-angiotensin system and sympathetic nervous system are linked by a positive feedback relationship 26. Insulin resistance, increased leptin and NEFA levels have been indicated to be possible factors augmenting sympathetic nervous activation in the metabolic syndrome 27. NEFA has been reported to raise blood pressure, heart rate, and α1-adrenoceptor vasoreactivity, while reducing baroreflex sensitivity, endothelium-dependent vasodilatation, and vascular compliance 28. Insulin resistance increases plasma leptin levels, and leptin has been reported to elevate sympathetic nervous activity, suggesting that leptin-dependent sympathetic nervous activation may contribute to an obesity-associated hypertension 29. Accumulating data suggest that metabolic syndrome is associated with markers of adrenergic overdrive 30.

In rats with the metabolic syndrome, induced by chronic consumption of a high fat, high refined sugar 31, hypertension is associated with oxidative stress 32, avid nitric oxide (NO) inactivation, and down-regulation of NO synthase (NOS) isoforms and endothelial NOS activator 32, suggesting that oxidative stress and endothelial dysfunction may be strongly associated with development of hypertension in the metabolic syndrome. Further, recent evidences suggest that oxidative stress, which is elevated in the metabolic syndrome 33, is associated with sodium retention and salt sensitivity 34.

In non-diabetic human subjects, lipid peroxidation, represented by plasma thiobarbituric acid reactive substance and urinary 8-epi-prostaglandin-F2α, were significantly and positively correlated with body mass index and waist circumference, indicating that fat accumulation is correlated with oxidative stress in humans 33. Cross-sectional data from 2,002 non-diabetic subjects of the community-based Framingham Offspring Study has shown that systemic oxidative stress is associated with insulin resistance 35. Insulin resistance induces an impairment in phosphatidylinositol 3-kinase (PI3K) – dependent signaling, which in endothelium may cause imbalance between production of nitric oxide and secretion of endothelin-1, leading to endothelial dysfunction 36. Epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction, which contributes to development of hypertension, and insulin resistance 36. In a prospective cohort study, each one-unit decrease of flow-mediated dilatation was associated with a significant 16% (95% confidence interval: 12–33%) increase in the multiple-adjusted relative risk of incident hypertension, suggesting that an impaired endothelial vasomotor function precedes and predicts the future development of hypertension 37.

The renin-angiotensin system (RAS) plays a crucial role in blood pressure regulation, by affecting renal function and by modulating vascular tone. The activity of the RAS appears to be regulated by food intake, and overfeeding of rodents has been reported to lead to increased formation of angiotensin II in adipocytes 38. Angiotensinogen, angiotensin converting enzyme, and type 1 angiotensin receptor gene are widely expressed in human adipose tissue 39, and production of angiotensin II and angiotensinogen in adipose tissue may be increased in obese subjects. Goodfriend TL, et al. measured plasma aldosterone levels in adults with various values of body mass index 40. Plasma aldosterone level was higher in obese subjects, but could not be explained by renin and potassium 40. The best predictor for plasma aldosterone level was abdominal obesity 40. Elevated renin and aldosterone levels have been observed in subjects with multiple risk factors as compared with those without multiple risk factors 41. Plasma aldosterone has been reported to be significantly associated with the metabolic syndrome and also with obesity-related hypertension 4243.

There are accumulating data indicating that angiotensin II inhibits the action of insulin via angiotensin type 1 receptor, in vascular muscle tissue, by interfering with insulin signaling through PI3K and its downstream protein kinase B (Akt) signaling pathway 44. This inhibitory action of angiotensin II is mediated through stimulation of RhoA activity and oxidative stress 44. Increased RhoA activity and reactive oxygen species inhibit PI3K/Akt signaling, resulting in decreased NO production in endothelial cell and increased vasoconstriction 44. Activated RAS may contribute to development of hypertension in the metabolic syndrome.

Recent cohort studies have demonstrated that high-sensitivity C-reactive protein (hsCRP) independently presents additive prognostic values at all levels of metabolic syndrome 45. Ridker PM, et al. suggest a consideration of adding hsCRP as a clinical criterion for metabolic syndrome 45. Abnormalities in inflammatory mediators have been also reported to be implicated with development of hypertension. A positive relationship between increased serum levels of CRP and the risk for development of incident hypertension in participants of the Women's Health Study 46. Grundy SM suggests a significant association among inflammation, hypertension, and the metabolic syndrome 47.

TNF-α is involved in the pathophysiology of hypertension in the metabolic syndrome. TNF-α stimulates the production of endothelin-1 and angiotensinogen 4849. The TNF-α gene locus seems to be involved in human insulin resistance-mediated hypertension 50. Serum TNF-α concentration has been reported to be positively correlated with systolic blood pressure and insulin resistance in humans 51, and increased TNF-α secretion has been observed in monocytes from hypertensive patients 52.

IL-6 is a multifunctional cytokine which mediates inflammatory responses. Recent study demonstrated that blood pressure was a significant and independent predictor of serum IL-6 concentrations in women 53. IL-6 stimulates the central nervous system and sympathetic nervous system, which may result in hypertension 5455. The administration of IL-6 leads to elevation in heart rate and serum norepinephrine levels in women 56. Further, IL-6 induces an increase in plasma angiotensinogen and angiotensin II 57, leading to development of hypertension.

Of 146 patients with OSA, 88 (60%) had the metabolic syndrome, whereas 33 of 82 patients (40%) without OSA had the metabolic syndrome, suggesting high prevalence of the metabolic syndrome in OSA patients 58. The proportion with hypertension was significantly higher in the OSA group (77%) than in the non-OSA group (51%), indicating a significant association between OSA and hypertension 58. Kono M et al. also demonstrated that the percentage of hypertensive patients were significantly higher in the OSA group (45%) than in the non-OSA group (15%) 59. There are accumulating evidences suggesting a significant association between the metabolic syndrome and OSA or its components 60. Patients with OSA are often considered to be obese, however, Kono M et al. reported that OSA was associated with hypertension, dyslipidemia, and hyperglycemia, independent of visceral obesity 59. Recent epidemiological and clinical data suggest a crucial role of OSA in development of hypertension, however, associations of OSA with insulin resistance and dyslipidemia are controversial 60. Visceral obesity remains a confounding issue in studying the association between OSA and the metabolic syndrome.

OSA is characterized by an increased number of sympathetic bursts, a raised plasma norepinephrine concentration, and a reduction in baroreflex sensitivity 232461, which leaves no doubt as to the existence of sympathetic activation induced by baroreflex dysfunction, much like what has been observed in the metabolic syndrome. In OSA, the nocturnal episodes of hypoxia and hypercapnia induce the stimulation of arterial chemoreceptors, which could induce sympathostimulating effects 61. Hyperleptinemia, insulin resistance, elevated angiotensin II and aldosterone levels, oxidative stress, inflammation, and endothelial dysfunction have been also suggested to be possible mechanisms whereby OSA may contribute to development of hypertension 62.