ROLE OF HYPERINSULINEMIA AND INSULIN RESISTANCE IN HYPERTENSION: METABOLIC SYNDROME REVISITED

Abstract

Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also called syndrome X. Support for this concept initially came from clinical and population studies showing correlations among hyperinsulinemia, insulin resistance and elevated BP in individuals with metabolic syndrome. Short-term studies in experimental animals and in humans provided additional evidence that hyperinsulinemia may evoke increases in sympathetic nervous system (SNS) activity and renal sodium retention that, if sustained, could increase BP. Although insulin infusions may increase SNS activity and modestly raise BP in rodents, chronic insulin administration does not significantly increase BP in lean or obese insulin resistant rabbits, dogs, horses, or humans. Multiple studies in humans and experimental animals have also shown that severe insulin resistance and hyperinsulinemia may occur in the absence of elevated BP. These observations question whether insulin resistance and hyperinsulinemia are major factors linking obesity/metabolic syndrome with hypertension. Other mechanisms, such as physical compression of the kidneys, activation of the renin-angiotensin-aldosterone system, hyperleptinemia, stimulation of the brain melanocortin system, and SNS activation appear to play a more critical role in initiating hypertension in obese subjects with metabolic syndrome. However, the metabolic effects of insulin resistance, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased BP to cause vascular and kidney injury which can exacerbate the hypertension and associated injury to the kidneys and cardiovascular system.

BRIEF SUMMARY

More than three decades ago hyperinsulinemia and insulin resistance were proposed as important contributors to elevated blood pressure (BP) in syndrome X/metabolic syndrome. Although insulin resistance and hyperinsulinemia are correlated with high BP, extensive studies in experimental animals and humans have provided little evidence that elevated insulin or insulin resistance directly mediate increased BP in metabolic syndrome, although the metabolic effects of insulin resistance may contribute to target organ injury and exacerbate hypertension.

INTRODUCTION

Cardiovascular (CV) diseases continue to be the main cause of mortality and morbidity worldwide. Despite major advances in diagnosis and treatment in the past 30–40 years, the prevalence of CV disease continues to increase in parallel with aging populations and ever growing prevalence of obesity and associated metabolic derangements¹. Elevated blood pressure (BP), even when not reaching defined cutoff levels that are considered to be diagnostic of hypertension, is a major risk factor for CV diseases including vascular injury, stroke, myocardial infarction, and heart failure^{2, 3}.

Although the causes of primary (essential) hypertension are not completely understood, excess adiposity appears to be a major culprit. Risk estimates from studies in multiple populations indicate that as much as 65–75% of the risk for primary hypertension can be attributed to excess weight gain and obesity⁴. However, the distribution of adipose tissue also appears to be important in determining the impact of obesity on BP and metabolic abnormalities such as dyslipidemia, insulin resistance, hyperinsulinemia, and diabetes mellitus^{5, 6} Experimental and clinical studies have provided strong evidence that excess visceral fat conveys much higher risk for CV disease and metabolic disorders compared to excess subcutaneous fat⁶.

The concept that CV disease is closely associated with a cluster of metabolic disorders was recognized more than 80 years ago when Banting and Best discovered insulin⁷. The interdependence of metabolic abnormalities, hypertension, and CV diseases was also described by physician scientists in the early and mid-1900’s and the term “metabolic syndrome” was introduced in the 1970’s^{8, 9}. In 1988, Gerald Reaven hypothesized that insulin resistance was the key factor underlying a group of metabolic disorders which included impaired glucose tolerance (IGT), hyperinsulinemia, high levels of very low-density lipoprotein (VLDL) triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, and hypertension¹⁰; Reaven coined the term “Syndrome X” to emphasize the unknown features of this group of disorders^{10, 11}. Norman Kaplan added central adiposity as a key driver of CV disease and named this cluster of disorders as the “deadly quartet”, consisting of visceral obesity, IGT/insulin resistance, hypertriglyceridemia, and hypertension¹². Other investigators used the term “insulin resistance syndrome” to emphasize what they believed to be the primary initiator of these cardiometabolic disorders^{13, 14}.

In this brief review we provide an update of the hypothesis that insulin resistance and compensatory hyperinsulinemia are primary mediators of elevated BP in metabolic syndrome and obesity, and then focus on other factors that may exert even greater impact on BP regulation in obesity/metabolic syndrome.

ROLE OF HYPERINSULINEMIA AND INSULIN RESISTANCE IN HYPERTENSION

Epidemiological Evidence Associating Insulin Resistance and Hyperinsulinemia with Hypertension

More than 30 years ago investigators observed that people with high plasma insulin concentration and insulin resistance often had higher BP compared to those with normal insulin levels^12–17. The majority of people with insulin resistance and hyperinsulinemia also exhibited a cluster of other metabolic abnormalities, including elevated serum triglycerides, dyslipidemia with low HDL and high low-density lipoproteins (LDL), among other factors. This “metabolic syndrome” included hypertension as a hallmark feature^18–20 (Table 1).

Table 1 -.

Clinical Definition of the Metabolic Syndrome. The criteria for an individual to be classified as having the metabolic syndrome include the presence of 3 or more of the following characteristics^18–20:

Measurement	Cutoff points
Increased waist circumference	Population- and country-specific definitions
Increased TG (drug treatment for elevated TG can be used as alternative indicator)	≥150 mg/dL (1.7 mmol/L)
Reduced HDL cholesterol (drug treatment for reduced HDL cholesterol can be used as alternative indicator)	≤40 mg/dL (1.0 mmol/L) in men; ≤50 mg/dL (1.3 mmol/L) in women
Increased BP (use of antihypertensive medication can be used as alternative indicator)	Systolic BP ≥130 mmHg and/or diastolic BP ≥85 mmHg
Increased fasting plasma glucose (drug treatment for increased plasma glucose levels can be used as alternative indicator)	>100 mg/dL (5.5 mmol/L)

BP, blood pressure; HDL, high density lipoprotein; TG, triglycerides.

Support for the concept that insulin resistance and hyperinsulinemia may mediate hypertension came from observations that these metabolic disorders were correlated with increased BP in non-obese as well as obese people. Ferrannini et al.²¹ reported that hyperinsulinemia was correlated with BP in non-obese subjects; however, the slope of the relationship between BP and plasma insulin concentration in 2,241 normotensive, non-diabetic subjects predicted that a 200 μU/mL increase in plasma insulin concentration could account for only a 1 mm Hg rise in BP²¹. These findings suggested minimal effects of insulin on BP in non-obese subjects. Other investigators found that plasma insulin concentrations are similar in non-diabetic normotensive and hypertensive people and that there was a tendency toward a negative correlation between insulin and BP²². After stratifying for obesity, the relationship between plasma insulin and BP is weak or nonexistent²³. Chen and colleagues²⁴, for example, found that, despite similar body mass index (BMI) and subcutaneous fat, obese insulin sensitive individuals exhibited lower systolic and diastolic BPs, higher HDL and lower triglycerides than their obese resistant counterparts. However, obese insulin sensitive individuals also had lower visceral and liver fat compared to their obese insulin resistant counterparts²⁴. Also, in most observational studies, including those in which insulin resistance was reported in non-obese people with hypertension, visceral adiposity was not assessed. Many people with hypertension and normal BMI may have increased visceral adiposity which can contribute to increased BP as well as to insulin resistance⁶. Therefore, despite the fact several population studies have reported an association between plasma insulin concentration, insulin resistance, BP and risk for developing hypertension, obesity (especially when associated with excess visceral fat) is often a confounding factor. Moreover, regardless of whether insulin and BP are correlated in obese or non-obese subjects, the quantitative importance of hyperinsulinemia and insulin resistance in causing hypertension cannot be established solely from cross sectional, or even longitudinal, correlational studies.

Some investigators have suggested that insulin resistance and compensatory hyperinsulinemia may be secondary to hypertension due to vascular rarefaction and increased peripheral vascular resistance which could reduce delivery of glucose and insulin to skeletal muscle thereby impairing glucose uptake²⁵. However, in many forms of secondary hypertension not associated with obesity, such as renovascular or mineralocorticoid hypertension, there is no evidence of insulin resistance²⁶. Moreover, most obese subjects with insulin resistance have normal or elevated skeletal muscle blood flow and insulin resistance appears to be related mainly to lipid accumulation and post-receptor signaling abnormalities^26–28.

Impact of Acute Hyperinsulinemia on Renal Sodium Excretion, SNS Activity and BP

Compensatory increases in plasma insulin levels in response to worsening insulin resistance have been proposed to trigger mechanisms that directly or indirectly increase renal sodium reabsorption^{29, 30} and sympathetic nervous system (SNS) activity^{31, 32}. If persistent, these changes could raise BP and eventually lead to hypertension in patients with syndrome X/metabolic syndrome.

Acute antinatriuretic effects of insulin.

Support for the concept that hyperinsulinemia may contribute to hypertension came from acute studies in which insulin was shown to have antinatriuretic effects. For example, acute insulin administration in humans can promote antinatriuresis^{33, 34}, while stopping insulin therapy in diabetic patients was associated with acute increases in sodium excretion³⁴. The antinatriuretric effect of acute hyperinsulinemia was also observed in isolated kidneys³⁵. These studies support the hypothesis that acute hyperinsulinemia can directly stimulate renal tubular sodium reabsorption, an effect that if sustained could translate into increased BP.

Acute effects of insulin to increase SNS activity.

Another mechanism proposed to mediate the effects of hyperinsulinemia on BP regulation is activation of the SNS. Excess caloric intake, commonly associated with development of insulin resistance and hyperinsulinemia, raises SNS activity^{31, 32, 36}, and acute insulin administration in humans to increase plasma insulin levels to those found in morbid obesity also increases skeletal muscle SNS activity^37–40. If this increase in muscle SNS activity is paralleled by increased SNS to CV relevant tissues, including the kidneys and vasculature, then insulin-mediated SNS activation may raise BP.

Although the mechanisms by which acute elevations in plasma insulin concentration promote sympathetic activation are not completely understood, insulin appears to have direct central nervous system (CNS) effects⁴¹. Insulin crosses the blood brain barrier, and acute injections of insulin into the cerebral ventricles or in specific brain nuclei increase SNS activity in rodents^42–45. Elevations in plasma insulin concentration during euglycemic-hyperinsulinemic clamp increase lumbar SNS activity^{46, 47} and this effect appears to be mediated by stimulation of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus and activation of glutamatergic neurons and melanocortin 4 receptor (MC4R) expressing neurons of the paraventricular nucleus (PVN)^{43, 47, 48}. Some of these direct CNS effects of insulin, however, may be influenced by sex hormones as males appear to be more sensitive than females, particularly in obese rodents⁴⁹.

Additional mechanisms have been proposed to contribute to insulin’s effects on BP regulation including insulin-mediated reduction in natriuretic peptides which appears to be accentuated in obesity⁵⁰ and loss of insulin-induced vasodilation which could potentiate the actions of insulin on BP^51–53. However, as discussed below, the acute actions of hyperinsulinemia on renal sodium handling and SNS activity do not appear to translate into elevations in BP.

Acute hyperinsulinemia does not raise BP.

Although acute increases in plasma or CNS insulin levels may promote sodium retention and increased SNS activity, almost invariably these acute studies have not demonstrated an effect of insulin in elevating BP. For example, acute hyperinsulinemia in healthy people increased forearm blood flow and reduced vascular resistance but did not alter BP when compared to baseline values before insulin infusion, despite evoking increases in skeletal muscle SNS activity³⁷. Even borderline hypertensive individuals who may be more sensitive to the pressor effects of insulin did not show elevations in BP during acute hyperinsulinemia despite insulin-mediated sympathoexcitation³⁸. Similar findings were observed in lean healthy rabbits, dogs and horses in which acute hyperinsulinemia during euglycemic-hyperinsulinemic clamp also failed to increase BP^54–56. In rodents, no significant elevation in BP was observed despite increased SNS activity during acute increases in plasma or CNS insulin concentrations^41–49.

It could be speculated that lean healthy humans and experimental animals do not resemble the milieu most commonly associated with hyperinsulinemia/insulin resistance including dyslipidemia, hyperglycemia, and other abnormalities caused by obesity such as impaired insulin-mediated vasodilation, reduced vascular nitric oxide (NO) availability, and impaired baroreflexes, which could amplify the effects of insulin to raise BP. The evidence, however, does not support this speculation. For instance, acute insulin administration in older adults who lacked insulin-mediated forearm vasodilation did not raise their BP⁵². Acute insulin administration in obese horses with metabolic syndrome also failed to evoke increases in BP⁵⁷, and in obese rats injected centrally with insulin, BP remained unaltered despite greater increases in lumbar SNS activity than in lean controls⁴⁹. Acute hyperinsulinemia in baroreceptor denervated or intact dogs caused no significant changes in BP⁵⁶. Thus, short-term hyperinsulinemia, due to acute systemic or CNS insulin administration, does not raise BP even in the presence of metabolic abnormalities associated with insulin resistance/metabolic syndrome in these animal models.

Impact of Chronic Hyperinsulinemia on Renal Sodium Excretion and BP Regulation

Although acute increases in plasma insulin concentration or direct intrarenal insulin infusion can elicit sodium retention and CNS injections of insulin can promote SNS activation, these effects do not appear to be sufficient to cause elevations in BP. It is possible, however, that chronic hyperinsulinemia associated with obesity/metabolic syndrome could contribute to hypertension if these effects on SNS activation and renal function were sustained.

Chronic hyperinsulinemia increases BP in rodents.

Chronic intravenous infusion of insulin in lean rats causes modest, but significant, increases in BP^{58, 59}. This increase in BP requires an intact renin-angiotensin-aldosterone system (RAAS)⁶⁰ and can be significantly attenuated by inhibiting thromboxane synthesis⁶¹, but is independent of adrenergic receptor activation⁶². Irsik et al.⁶³ also showed that chronic intrarenal infusion of insulin, at a dose that did not significantly alter circulating insulin levels, caused increases in BP similar to those observed with larger doses of systemically infused insulin, and that this pressor effect was not associated with activation of the RAAS. Other investigators also reported that chronic systemic insulin infusions in lean rats is associated with increased sensitivity to adrenergic stimulation and impaired reflex inhibition of splanchnic nerve activity⁶⁴. These observations suggest that in rats hyperinsulinemia may elicit modest, sustained increases in BP. However, as discussed below, results from studies in larger experimental animals and humans do not corroborate these observations in rodents.

Evidence against a major role for hyperinsulinemia/insulin resistance in initiating hypertension.

Although previous studies demonstrated that chronic insulin infusion in rats can increase BP, studies in other experimental animals as well as in humans show that chronic hyperinsulinemia, even in the presence of metabolic syndrome/insulin resistance, does not cause hypertension. In humans, the correlation between plasma insulin levels and BP is usually confounded by visceral obesity that often precedes insulin resistance and hyperinsulinemia. For instance, the higher BP observed in insulin resistant individuals compared to insulin sensitive subjects with similar BMI is confounded by reduced visceral adiposity and liver fat infiltration in the insulin sensitive group²⁴. The positive correlations between changes in fasting insulin, insulin sensitivity, and risk of developing hypertension are lost after adjusting for BMI or waist circumference⁶⁵; and when a positive correlation between insulin levels and BP still remains after adjusting for obesity it is often very modest (only 1 mmHg BP for each 200 μU/mL increment in insulin level¹³).

Stronger evidence that insulin may not be a major hypertensive factor in humans comes from studies in insulinoma patients who are not hypertensive despite severe hyperinsulinemia^{66, 67}, even when they become resistant to the metabolic/vasodilatory effects of insulin^{68, 69}. Also, patients with type 1 diabetes exhibited reduced rather than increased BP during a 15-month follow-up treatment with continuous subcutaneous insulin infusion⁷⁰.

Contrary to what has been demonstrated in rodents, insulin does not appear to play a critical role in long-term BP regulation in other experimental animals. Administration of an insulin antagonist in hypertensive and hyperinsulinemic obese rabbits resulted in only modest attenuation of hypertension⁷¹. In addition to the lack of a pressor effect of acute hyperinsulinemia to elevate BP in lean or obese dogs and horses discussed previously, intravenous insulin infusions for several days or even weeks in lean healthy dogs did not raise BP^72–75. When insulin was chronically infused directly into the renal arteries of conscious dogs, no increase in BP was observed and the dogs exhibited only mild transient sodium retention⁷⁶. Chronic insulin infusions directly into the CNS via the carotid or vertebral arteries of conscious dogs also failed to increase BP⁷⁷.

Although insulin infusion has been reported to increase SNS activity without raising BP in several species, including humans, at least part of the sympathetic activation may be a compensatory response to the vasodilator effects of insulin. Insulin infusion in humans causes vasodilation of skeletal muscle³⁷ and chronic intravenous insulin administration in dogs decreased total peripheral vascular resistance, increased cardiac output, and increased HR, which may suggest compensatory activation of the SNS^{75, 78}. Thus, it is possible that insulin’s action to cause systemic vasodilation may trigger reflex activation of the SNS to buffer a potential fall in BP caused by its vasodilatory effects. In fact, patients with autonomic insufficiency and/or impaired baroreflex show greater vasodilation in response to insulin and more pronounced reductions in BP^{79, 80}. These studies suggest that insulin may not cause sustained increases in SNS activity to CV relevant tissues via direct actions in the CNS and that its hypertensive effects in rodents are largely mediated by action on peripheral tissues, such as the kidneys^{63, 81}.

In obesity/metabolic syndrome the vasodilator effects of insulin are attenuated⁸² and it has been suggested that vascular insulin resistance and impaired vasodilation may be required for hyperinsulinemia to cause hypertension. However, obese insulin resistant dogs exhibited no significant increases in BP during chronic insulin infusions that raised their already high baseline insulin levels⁸³. This failure of insulin to raise BP occurred despite impaired insulin-mediated vasodilation⁸³. Moreover, hypertensive dogs infused chronically with angiotensin II (Ang II) did not show potentiated BP responses to insulin when compared to Ang II infusion alone⁷³. This suggests that obesity-induced activation of the RAAS does not interact additively or synergistically with insulin to increase BP. Similar findings were obtained in dogs infused chronically with norepinephrine, to mimic the increased adrenergic activity that is also commonly observed in obese/metabolic syndrome patients⁷⁴. Chronic insulin infusion in dogs with 70% reduction in kidney mass and fed high sodium diet, to increase their susceptibility to hypertensive stimuli, also did not raise BP⁷³. Therefore, even with a background of insulin resistance, dyslipidemia, increased Ang II, increased adrenergic activity, and cardiorenal dysfunction, chronic hyperinsulinemia failed to significantly increase BP in obese dogs.

Overall, as summarized in Table 2 and Figure 1, most previous studies suggest that insulin resistance and hyperinsulinemia do not play a major role in initiating hypertension associated with obesity/metabolic syndrome in humans or large experimental animals such as dogs and horses. However, chronic insulin administration may cause modest increases in BP in rodents. Yet, as discussed later, several studies have also shown that severe insulin resistance and hyperinsulinemia may not lead to hypertension even in rodents when there is morbid obesity due to deficiency of the leptin-POMC-MC4R pathway.

Table 2 -.

Differential impact of insulin infusion on blood pressure regulation in humans and experimental animal models.

Model	Effects
Humans
Lean	Increased SNS activity (acute) Increased Na+ retention (acute) Vasodilation No change in BP (acute or chronic)
Obese	Increased SNS activity (acute) Increased Na+ retention (acute) Attenuated vasodilation (acute) No increase in BP (acute or chronic)
Horses
Lean	No change in BP
Obese	No change in BP
Dogs
Lean	Increased Na+ retention (acute) Vasodilation No increase in BP (acute or chronic)
Obese	Increased Na+ retention (acute) Attenuated vasodilation No increase in BP (acute or chronic)
Rabbits
Lean	Increased SNS activity (acute) No change in BP (acute)
Obese	Modest contribution to elevated BP
Rats
Lean	Increased SNS activity (acute) No change in BP (acute) Modest increase in BP (chronic)
Obese	Increased SNS activity (acute) No change in BP (acute) Modest increase in BP (chronic)

BP, blood pressure; Na+, sodium; SNS, sympathetic nervous system.

Figure 1 -. Main actions of insulin on BP regulation.

This figure summarizes the main effects of hyperinsulinemia on blood pressure regulation that have been proposed and the evidence from studies in humans and several experimental animal models supporting or refuting these hypothesized effects. BP, blood pressure; Na+, sodium; SNS, sympathetic nervous system.

MECHANISMS THAT INITIATE HYPERTENSION IN OBESITY AND METABOLIC SYNDROME

The list of additional factors, besides insulin resistance and hyperinsulinemia, that have been postulated to mediate hypertension on obesity/metabolic syndrome is extensive and includes various adipokines from adipose tissue, abnormal gut microbiota, SNS activation, excess antinatriuretic hormones, deficiency of natriuretic hormones, vascular and kidney dysfunction, and others mechanisms that have been previously reviewed^84–87. For many of these factors, however, clear cause and effect relationships with increased BP have not been established.

Studies in experimental animals and in humans indicate that hypertension associated with obesity/metabolic syndrome is initiated by multiple factors that increase renal sodium reabsorption and cause expansion of extracellular fluid volume^{84, 88}. Three mechanisms appear to be especially important in initiating these renal changes and hypertension associated with visceral obesity: 1) physical compression of the kidneys by fat in and around the kidneys, 2) activation of the RAAS, and 3) increased SNS activity. With prolonged obesity over several years, elevated BP interacts synergistically with metabolic abnormalities, especially hyperglycemia and hyperlipidemia, to cause kidney and cardiovascular injury which exacerbates hypertension and injury to the CV system and kidneys^{89, 90}. We have previously discussed the importance of these mechanisms^{84, 91, 92} and therefore briefly outline them in this review.

Compression of the Kidneys by Visceral, Perirenal and Renal Sinus Fat

In obese dogs, rabbits and humans, but not in rodents, perirenal fat often encapsulates the kidneys, adheres tightly to the renal capsule, and invades the renal sinuses, causing kidney compression and increased intrarenal pressures which, in turn, raises BP⁹¹. In patients with visceral obesity, intra-abdominal pressures also rise in proportion to sagittal abdominal diameter, further compressing the kidneys⁹³. Population studies indicate that visceral obesity and especially retroperitoneal and renal sinus fat are uniquely correlated with incident hypertension^94–96. Also, fatty kidneys are associated with increased risk for chronic kidney disease (CKD) even after adjustment for BMI and visceral adiposity⁹⁵.

Compression of the kidneys by fat around the kidneys and in the renal sinuses raises intrarenal pressure to as high as 19 mmHg in obese dogs⁸⁴ and perhaps even higher in people with severe abdominal obesity⁹³. High intrarenal pressures compress the vasa recta capillaries and thin loops of Henle, reducing blood flow in the renal medulla, increasing sodium reabsorption in the loop of Henle, and contributing to volume expansion and hypertension. Increased sodium reabsorption in the loop of Henle sodium would also tend to reduce sodium chloride delivery to the macula densa, causing feedback mediated renal vasodilation, increased glomerular filtration rate (hyperfiltration), and increased renin secretion – phenotypes that are characteristic of obesity-associated hypertension prior to renal injury and eventual loss of nephrons⁸⁴

Although excess fat in and around the kidneys cannot explain rapid increases in BP that occur shortly after increased caloric intake and weight gain, kidney compression and “lipotoxic” effects of kidney fat may help explain why visceral adiposity is much better correlated with hypertension than is subcutaneous adiposity^{5, 6, 84}.

RAAS Activation in Obesity/Metabolic Syndrome

The RAAS is the most powerful hormonal system for regulating renal sodium excretion and plays a critical role in BP regulation⁹⁷. Excess weight gain, especially when associated with increased visceral adiposity, causes mild to moderate increases in several components of the RAAS, including Ang II and aldosterone^{91, 98}. Even with only modest activation of the RAAS, blockade of Ang II receptors or angiotensin converting enzyme (ACE), or mineralocorticoid receptor (MR) antagonism attenuates sodium retention, volume expansion, and increased BP in obesity^{84, 91, 99}. Thus, obesity appears to increase BP sensitivity to RAAS activation¹⁰⁰.

MR antagonism may also reduce BP and protect the kidneys from injury through mechanisms that are at least partly independent of aldosterone. For example, administration of the MR antagonist spironolactone in obese patients and patients with treatment-resistant hypertension caused reductions in BP that did not correlate with circulating aldosterone levels^101–103. In obese hypertensive patients treated with ACE inhibitors, addition of spironolactone to their treatment regimen further reduced BP indicating that MR antagonism reduces BP in obesity despite prior blockade of Ang II formation¹⁰¹.

Although the mechanisms responsible for aldosterone-independent MR activation in obesity are still unclear there is evidence that obesity and its associated metabolic disorders may increase Rac1, a GTP-binding protein that stimulates MR signaling¹⁰⁴. Other studies suggest that oxidative stress and cortisol may activate MR in obesity due to downregulation of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)^{91, 105, 106}; this enzyme normally converts cortisol, which can activate the MR, to inactive cortisone in the renal tubular cells¹⁰⁶. Although the mechanisms by which MR is activated in obesity are not fully understood, MR antagonism is clearly an effective treatment for obese patients with hypertension that are resistant to antihypertensive therapy^{101–103, 107, 108}.

Sympathetic Nervous System Activation in Obesity/Metabolic Syndrome

The importance of SNS activation in contributing to hypertension in obesity/metabolic syndrome has been clearly documented^{109, 110}. Increases in sympathetic nerve activity in obese experimental animals and in humans are often modest and do not reduce tissue blood flow. However, increased renal sympathetic activity is sufficient to increase sodium reabsorption and renin secretion. Moreover, renal denervation greatly attenuates sodium retention and hypertension in obese experimental animals as well as obese humans with metabolic syndrome^111–113.

Multiple factors have been proposed to stimulate SNS activity in obesity. The roles of some of these factors, such as insulin resistance, hyperinsulinemia, fatty acids and Ang II, are beyond the scope of this review and have previously been discussed^{5, 109, 114}. Some of the more important factors that may contribute to SNS activation in obesity include impaired baroreceptor reflexes, activation of chemoreceptors, especially in patients with obstructive sleep apnea and hypoxemia, and hyperleptinemia with activation of the CNS POMC-MC4R pathway^{84, 109, 115, 116}.

Hyperleptinemia and activation of CNS melanocortin system in obesity/metabolic syndrome.

Leptin, the product of the ob/ob gene, is secreted by adipocytes in proportion to the degree of adiposity and obese individuals exhibit higher plasma leptin concentrations than lean people¹¹⁷. There is a positive correlation between plasma leptin concentration, skeletal muscle SNS activity, and BP in humans¹¹⁸. Moreover, acute leptin administration increases SNS activity to various tissues including the kidneys, brown adipose tissue, skeletal muscle, and adrenal glands in rodents^{119, 120}. Leptin also increases skeletal muscle SNS activity in humans¹²¹. Acute leptin infusions, however, often have minimal effect on BP in rodents or humans despite increasing SNS activity, likely due to counterbalancing vasodilator effects of NO, also stimulated by leptin¹²², and the fact the hypertensive effects of leptin are slow in onset, requiring several days to occur¹²³.

In lean rodents, chronic leptin administration to raise leptin concentration to that observed in severe obesity causes sustained, albeit modest, increases in BP^122–124 which can be blocked by adrenergic receptor antagonism in male rodents and markedly attenuated by MR antagonism in females^125–128. The hypertensive effects of leptin are exacerbated in animals with reduced NO availability¹²² as often occurs in obese patients with endothelial injury and atherosclerosis. Further support for a role of hyperleptinemia in contributing to elevated BP in obesity also comes from studies showing significant attenuation of the hypertension in obese rabbits treated with leptin receptor antagonist⁷¹.

Although studies of the chronic BP effects of leptin in humans are limited, people with leptin gene or leptin receptor mutations are extremely obese with many characteristics of the metabolic syndrome, including marked hyperinsulinemia and severe insulin resistance, but they are not hypertensive¹²⁹. Despite severe obesity, these patients also appear to have sympathetic hypofunction, postural hypotension, attenuated RAAS responses to upright posture, and reduced BP responses to cold pressor tests¹²⁹. Similar findings have been reported in male leptin deficient (ob/ob) mice which have severe obesity, insulin resistance, hyperinsulinemia, and dyslipidemia but lower BP and reduced SNS activity compared to lean mice^{128, 130}; and leptin infusion in ob/ob mice increased BP despite reducing body weight¹³¹. These observations collectively support a role for leptin as an important link between obesity/metabolic syndrome, increased SNS activity and elevated BP.

One mechanism by which leptin raises BP is by stimulating the brain POMC neuron-MC4R pathway^{92, 132}. The CNS POMC-MC4R pathway regulates appetite, energy expenditure and body weight¹³³. POMC-expressing neurons, located in hypothalamus and brainstem, send projections to second order neurons where they release α-melanocyte stimulating hormone (α-MSH), an agonist for MC4R¹³³. MC4R are located in several regions of the CNS but are particularly abundant in areas that participate in cardiovascular regulation including the hypothalamus, brainstem, and spinal cord^{92, 134, 135}.

Genetic deletion of leptin receptors on POMC neurons, MC4R deficiency, or pharmacological blockade of MC4R all completely abolish the rise in BP observed during chronic leptin infusion^{124, 132, 136}. Also, MC4R activation using synthetic or natural agonists injected into the CNS raises SNS to various tissues including the kidneys^{137, 138} and chronic activation of brain MC4R evokes sustained elevations in BP in rodents^{139, 140}. MC4R-induced elevations in BP are also observed in lean and obese humans treated with MC4R agonists^{134, 135, 141, 142}. Perhaps the most compelling evidence for a role of MC4R in obesity/metabolic syndrome-induced hypertension is the finding that patients with loss-of-function mutations of the POMC gene, genes involved in POMC processing, or MC4R gene have severe obesity and most features of the metabolic syndrome but are less likely to develop hypertension than less obese individuals with normal POMC-MC4R genotypes^{141, 142}. Humans with MC4R mutations also have attenuated SNS responses to stimuli that increase SNS activity such as inspiratory hypoxia¹⁴³.

The attenuated SNS response and lower BP in humans with POMC/MC4R mutations despite severe insulin resistance, impaired IGT, hyperinsulinemia and dyslipidemia also suggest that insulin resistance and hyperinsulinemia are not the primary drivers of hypertension in obesity/metabolic syndrome.

CONCLUSIONS

Obesity/metabolic syndrome is a major risk factor for multiple chronic diseases including CV diseases. Many hypotheses have been proposed to explain how excess adiposity increases SNS activity, impairs kidney function, and elevates BP. One hypothesis that gained traction more than 30 years ago is that hyperinsulinemia and insulin resistance are major contributors to hypertension in people with obesity/metabolic syndrome. This hypothesis is mainly supported by epidemiological studies showing positive correlations among plasma insulin concentration, insulin resistance, and BP and from studies in rodents. Although hyperinsulinemia and insulin resistance are major players in other disturbances that occur in metabolic syndrome (e.g., dyslipidemia and dysglycemia) and may increase the risk for CV disease, there is strong evidence from studies in humans and experimental animals that hyperinsulinemia, with or without insulin resistance, does not play a major role in initiating hypertension in obesity/metabolic syndrome. As summarized in Figure 2, other factors such as physical compression of the kidneys, RAAS activation, SNS activation, hyperleptinemia, and activation of brain MC4R have been demonstrated to be critical in linking excess visceral adiposity with increased BP associated with obesity/metabolic syndrome. Although hyperinsulinemia may not initiate obesity hypertension, hyperglycemia and dyslipidemia associated with insulin resistance likely contribute to progressive vascular and kidney injury which, over the long-term, can exacerbate hypertension and lead to further target organ injury. The precise mechanisms by which the metabolic syndrome contributes to hypertension and progressive target organ injury are not completely understood and remain an important area for research, especially considering the ever growing prevalence of obesity and the limited effectiveness of current therapies for many of the associated metabolic disorders.

Figure 2 -. Potential mechanisms of hypertension and cardiovascular and renal injury in obesity.

Obesity, particularly visceral obesity, triggers activation of the renin-angiotensin-aldosterone system (RAAS) which together with increased sympathetic nervous system (SNS) activity increases renal sodium reabsorption and blood pressure. Physical compression of the kidneys caused by increased fat in and around the kidneys may also stimulate renal sodium reabsorption and contribute to RAAS activation in obesity. When obesity is sustained, progressive metabolic impairments including insulin resistance, compensatory hyperinsulinemia, and accompanying hyperglycemia and dyslipidemia may contribute to inflammation and atherosclerosis and interact with hypertension to cause further injury to the kidneys and cardiovascular system that worsens the hypertension and creates a vicious cycle.