Obesity hypertension: role of leptin and sympathetic nervous system^*

Abstract

Obesity may account for as much as 65% to 75% of human essential hypertension in most industrialized countries. Excess renal sodium reabsorption and a hypertensive shift of renal-pressure natriuresis play a key role in mediating obesity hypertension. Sympathetic activation contributes to obesity-induced sodium retention and hypertension because adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with other neurochemical pathways in the hypothalamus may be a partial link between excess weight gain and increased sympathetic activity. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term intravenous leptin infusions in nonobese rodents at rates that raise plasma concentrations to the levels found in severe obesity increase arterial pressure and heart rate through adrenergic activation. Also, transgenic mice that overexpress leptin develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including melanocortin-4 receptors. However, it is unclear whether this pathway or others, such as neuropeptide Y, mediate the long-term effects of leptin on blood pressure. In addition, leptin has other actions, such as stimulation of nitric oxide formation and enhancement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the precise role of these complex interactions in human obesity has not been elucidated, this is an important area for further investigation, especially considering the current epidemic of obesity in most industrialized countries. Am J Hypertens 2001;14:103S–115S © 2001 American Journal of Hypertension, Ltd.

Obesity, leptin, sympathetic nervous system, insulin, fatty acids, angiotensin, kidney, sodium excretion

Cardiovascular morbidity and mortality increase substantially as body mass index (BMI) rises above 25 kg/m²,^1,2 and many health experts consider persons who have a BMI above this level to be overweight. By this definition, over 50% of adults population in the United States are overweight.³ Similar statistics exist for other industrialized countries, leading nutrition experts to declare an “epidemic” of obesity.⁴

Obesity initiates a cluster of cardiovascular, renal, and metabolic disorders that has been referred to as Syndrome X, the metabolic syndrome, the insulin resistance syndrome, and the deadly quartet. However, considerable evidence indicates that excess weight gain is the root cause for virtually all of the abnormalities associated with this syndrome, including hypertension.

Essential hypertension is closely related to excess weight gain

One important consequence of excess body weight is increased risk for hypertension. Experimental studies in animals have shown that excess weight gain due to a chronic high-fat diet almost invariably raises blood pressure.^5–7 Clinical studies have documented the effectiveness of weight loss in lowering blood pressure in normotensive and hypertensive obese subjects, even when sodium intake is prevented from decreasing.^2,8 Finally, studies in populations throughout the world have shown that obesity is a major risk factor for development of hypertension.^2,9,10,11 Lean populations rarely have significant hypertension, whereas hypertension is common in overweight people in diverse populations,² suggesting that obesity and hypertension are inextricably linked. Although the precise contribution of excess weight in causing human essential hypertension has not been determined in different ethnic groups, it is clear that most (75% to 80%) essential hypertensive people are overweight. Moreover, risk estimates from the Framingham Heart Study suggest that approximately 78% of the risk for essential hypertension in men and 65% in women can be attributed to obesity.¹⁰

This close association between BMI and blood pressure is especially impressive when one considers that BMI, although correlated with obesity, is not a direct marker of adiposity. For example, it is possible to have a high BMI because of increased muscularity, although there is no evidence that increasing skeletal muscle mass raises cardiovascular risk. Also, BMI does not take into account the body fat distribution which appears to confer considerable risk for metabolic abnormalities and cardiovascular disease; hypertension is much more prevalent in persons with central compared with lower body obesity.¹² However, BMI and arterial pressure are associated even in nonobese, lean populations,⁹ suggesting that the effect of weight gain on blood pressure regulation may be more complex than can be explained simply by increasing adiposity.

Why are some obese people normotensive, whereas most are hypertensive?

The observation that some obese people are not hypertensive (according to the standard criteria of a systolic/diastolic blood pressure >140/90 mm Hg) has led to the belief that there are large genetically determined variations in the blood pressure responses to weight gain. This concept seems to be consistent with the fact that some populations, such as the Pima Indians in the Southwestern United States, have a high prevalence of obesity but may not have corresponding high rates of hypertension until diabetic nephropathy occurs.¹¹ African American females have also been suggested to have a lower risk of hypertension than white females with the same degree of obesity.¹¹

Another explanation, however, is that most persons experience increased blood pressure with weight gain but other factors (eg, genetic) influence baseline blood pressure measured before weight gain. Thus, an overweight person who had lower than average baseline blood pressure before excess weight gain may not be classified as hypertensive (>140/90 mm Hg) even though arterial pressure and the risk for cardiovascular disease are higher than before the weight gain. On a population basis, however, weight gain shifts the frequency distribution so that a much higher fraction of obese subjects are hypertensive compared with lean subjects. Therefore, obese persons with normal blood pressure (<140/90 mm Hg) are probably hypertensive relative to their baseline blood pressure and perhaps should be considered for antihypertensive therapy. In fact, most of the population risk for cardiovascular disease occurs at blood pressures lower than 140/90 mm Hg and obesity adds to this risk. This explanation is consistent with the finding that weight loss usually reduces blood pressure in normotensive as well as in hypertensive obese subjects.² This also fits with the observation that weight gain almost invariably increases blood pressure in humans and experimental animals.¹³

Animal models of obesity

Experimental studies in animals allow a mechanistic approach to the problem of obesity hypertension. Although there are many rodent models of genetic obesity, the cardiovascular and renal changes in most of these genetic models have not been well characterized (Table 1). Those that have been studied sometimes do not mimic the cardiovascular, renal, and neurohumoral changes found in obese humans. For example, the Zucker fatty rat, a widely used model of genetic obesity, has decreased plasma renin activity,¹⁴ whereas obese humans often have increased plasma renin activity.¹⁵ Also, increased sympathetic activity appears to play a significant role in causing hypertension in obese people¹⁶ but not in Zucker fatty rats.¹⁴

Table 1

Cardiovascular, neurohumoral, and renal characteristics of some dietary and genetic models of obesity

Model	Blood Pressure	Cardiac Output	Heart Rate	Sympathetic Activity	PRA	GFR*
Dietary (high-fat diet)
Human (diet/genetic?)	↑	↑	↑	↑	↑	↑
Dog	↑	↑	↑	↑	↑	↑
Rabbits	↑	↑	↑	↑	↑	↑
Sprague-Dawley Rat	↑	↑	↑	↑	↑	?
Rodent Genetic-High Fat Diet Sensitive Models
Osborne-Mendel Rat	↑(slight)	?	↔	↔	↓	?
AKR/J Mouse	?	?	?	?	?	?
Rodent Genetic-Spontaneous Obesity-Autosomal Recessive
Zucker Fatty Rat (fa/fa)	↑ (slight)	?	↓	↓	↓	↑
Wistar Fatty Rat (fa/fa)	↑	?	?	↑	±	?
Koletsky SHR (fak)	↓**	?	?	?	?	?
LA/NIH-corpulent rat (cp/cp)	↔	?	?	?	?	?
SHR/NIH-corpulent rat (cp/cp)	↔***	?	?	?	?	?
Dahl SS/NIH-corpulent rat (cp/cp)	↔***	?	?	?	?	↓
Otsuka Long-Evan Tokushima Fatty Rat (OLETF)	↑	?	?	?	?	↑
Obese Mouse (ob/ob)	↓	?	?	?	?	?
Diabetic Mouse (db/db)	?	?	?	?	?	?
Tubby Mouse (tub/tub)	?	?	?	?	?	?
Rodent Genetic-Spontaneous Obesity-Dominant
Yellow Agouti mouse (Ay/a)	↑	?	?	?	?	?
Rodent Genetic-Spontaneous Obesity-Polygenic Inbred
New Zealand Obese Mouse	↑	?	?	?	?	?
Japanese Mouse (KK)	?	?	?	?	?	?
The Sand Rat (Psammomys obesus)	↔	↔	↔	?	?	↑

PRA = plasma renin activity; GFR = glomerular filtration rate.

*

Obesity often causes renal injury and loss of nephron function; the GFR changes indicated refer to the early phases of obesity, before major loss of nephron function has occurred.

**

In the Koletsky SHR, obese rats have high blood pressure, but on low salt intake blood pressure is lower than in lean SHR.

***

Blood pressures in SHR/NIH-corpulent and Dahl SS/NIH-corpulent rats are increased, but not higher than lean SHR and lean Dahl SS rats, respectively.

An interesting model of genetic obesity is the leptin-deficient ob/ob mouse.¹⁷ These mice are obese because of an inability to produce leptin and have reduced sympathetic activity compared with their lean counterparts. When fed a low-salt diet, ob/ob mice actually have lower blood pressures than their lean counterparts.¹⁸ Because increased leptin production may be an important mediator of sympathetic activation and hypertension in obesity,^19,20 leptin deficiency may prevent the effects of increased adiposity to raise blood pressure in these mice. Some rodent models of obesity that have defective leptin receptors, such as Koletsky (fa^k/fa^k) obese spontaneously hypertensive rats, also have lower blood pressures than their lean controls when placed on a low-sodium diet.²¹ These observations suggest that important pathways normally linking obesity to hypertension, such as leptin, are absent in some of the genetic models of obesity.

In contrast to genetic models of obesity, dietary models of obesity often closely mimic the responses to excess weight gain in humans (Table 1).^22–24 For example, rabbits and dogs fed a high-fat diet demonstrate rapid weight gain and increased arterial pressure that depends, in part, on increased adrenergic activity.^23,25,26 Obesity caused by feeding a high-fat diet is also associated with other cardiovascular, renal, endocrine, and metabolic changes similar to those found in most obese humans.^23–28 These observations lend credence to the hypothesis that dietary factors, especially a high-fat diet, have a major role in causing human obesity.

Obesity hypertension: cardiovascular and renal mechanisms

Hemodynamic responses to excess weight gain

Obesity is associated with increases in regional blood flows, cardiac output, and arterial pressure in experimental animals and humans.^5,6,23,24 In dogs placed on a high-fat diet for 5 weeks with a constant intake of sodium, protein, and carbohydrates, there were parallel increases in body weight and blood pressure, with arterial pressure increasing 15 to 20 mm Hg.⁵ This is similar to the modest changes in blood pressure observed in the first few weeks after rapid weight gain or weight loss in humans. A high-fat diet in dogs also markedly raised heart rate and cardiac output, with little change in stroke volume.⁵ Although weight gain increases sympathetic tone, as discussed below, the rise in resting heart rate in obese humans and obese dogs is due primarily to withdrawal of parasympathetic tone.²⁵

Weight gain increases regional blood flows and cardiac output, and causes cardiovascular hypertrophy/remodeling

Studies in humans and experimental animals indicate that obesity is associated with extracellular volume expansion and increased regional blood flows that summate to raise cardiac output.^2,5,24 Although part of the increased cardiac output is due to additional blood flow required for the extra adipose tissue, blood flows in nonadipose tissue, including the heart, kidneys, gastrointestinal tract, and skeletal muscle, also increase with weight gain.^5,6,28 The mechanisms responsible for increased regional blood flows are likely due, in part, to increased metabolic rate and local accumulation of local vasodilator metabolites as well as growth of the organs and tissues in response to their increased metabolic demands. Increased blood flow occurs in many tissues despite elevated sympathetic activity. Apparently, adrenergic activity is not increased sufficiently to override the vasodilator influences associated with obesity, and blood flow is increased in many tissues.

Along with increased cardiac output, there is cardiac hypertrophy and remodeling as well as impaired cardiac systolic and diastolic function in obese compared with lean subjects. In animals fed a high-fat diet for 5 to 12 weeks, cardiac filling pressures were increased and diastolic dysfunction was evident even at this early stage of obesity.²⁹ Clinical studies also indicate that cardiac hypertrophy is more severe in obese than in lean subjects with comparable hypertension.³⁰ High sodium intake, which often occurs concurrently with high caloric intake, also exacerbates obesity-induced cardiac hypertrophy through mechanisms that are at least partly independent in increases in arterial pressure.³¹ Thus, obesity not only causes cardiac hypertrophy by itself, but also amplifies cardiac growth and fibrosis caused by other stimuli, such as increased blood pressure and high salt intake.

Abnormal kidney function in obesity

Abnormal kidney function, manifested as a hypertensive shift of pressure natriuresis, has a central role in all forms of hypertension studied thus far.³² Obesity hypertension is no exception, with increased arterial pressure required to maintain sodium balance.³³ In dogs fed a high-fat diet, there was marked renal sodium retention as well as increased extracellular fluid volume, much more than could be accounted for by the increased adipose tissue.²³ Similar findings have been reported in obese people.²⁴ Sodium retention and volume expansion in obesity are not due to renal vasoconstriction or decreased glomerular filtration rate (GFR), as GFR and renal plasma flow are elevated in obese animals³³ and humans²⁷ compared with lean control subjects. Renal sodium retention is due mainly to increased tubular reabsorption, at least in the early phases of the obesity, before glomerular injury and loss of nephron function.³³

Increased tubular reabsorption and impaired pressure natriuresis in obesity appear to be caused by multiple mechanisms, including: 1) activation of the renin-angiotensin system,^15,23 2) physical compression of the kidneys,^13,33 and 3) increased renal sympathetic nerve activity.^16,23 In this article, we consider mainly the role of the sympathetic nervous system.

Abnormal kidney function is not only a cause but also a consequence of obesity. Even in the early stages of obesity, there are structural as well as functional abnormalities of the renal medulla and cortex.^23,34,35 These changes, which we have previously reviewed,³⁶ may be the precursors of more serious renal injury that not only worsens the hypertension but may also progress to end-stage renal disease.

Sympathetic nervous system activation in obesity hypertension

Direct and indirect methods suggest that sympathetic activity is higher in obese than in lean subjects. For example, high caloric intake increases norepinephrine turnover in peripheral tissues and raises resting plasma norepinephrine concentration.^16,37,38 High caloric intake also amplifies the rise in plasma norepinephrine associated with stimuli such as upright posture and isometric hand grip.¹⁶ Obese hypertensive subjects also have increased muscle sympathetic activity, measured directly with microneurographic methods, compared with lean subjects.^39,40 Moreover, weight loss markedly reduces sympathetic activity in obese subjects.⁴¹ Although there may be some variation in regional sympathetic activation, sympathetic activity is increase in several organs and tissues, including the kidneys, of obese compared with lean humans.^37,40 Interestingly, Pima Indians have an attenuated increase in sympathetic activity with increasing adiposity, and this has been suggested to contribute to the lower prevalence of hypertension found in this population.⁴²

Sympathetic blockade attenuates obesity hypertension

Sympathetic activation appears to contribute to hypertension in experimental as well as human obesity. In dogs fed a high-fat diet, combined α- and β-adrenergic blockade lowered blood pressure to a much greater extent in obese than in lean dogs.⁴³ Also, combined α- and β-adrenergic blockade markedly attenuated the rise in blood pressure that occurred in dogs as well as rabbits fed a high-fat diet for several weeks.^26,43 Clonidine, a drug that stimulates central α2 receptors and reduces sympathetic activity, also markedly blunted the hypertension in dogs fed a high-fat diet.⁷ Finally, combined α- and β-adrenergic blockade for 1 month reduced blood pressure to a greater extent in obese than in lean essential hypertensive patients.⁴⁴ All of these findings indicate that sympathetic activation has an important role in raising blood pressure in obese subjects.

Renal sympathetic nerves mediate sodium retention and hypertension in obesity

Sympathetic activation raises blood pressure and causes sodium retention in obesity mainly through the renal nerves. In dogs fed a high-fat diet, the renal nerves appear to be essential for the sodium retention and hypertension associated with obesity. Kidneys with intact renal nerves retained almost twice as much sodium as denervated kidneys, and bilateral renal denervation greatly attenuated sodium retention and hypertension in dogs fed a high-fat diet (Fig. 1).⁴⁵ Thus, the renal nerves mediate an important part of the sodium retention, impaired renal-pressure natriuresis, and hypertension associated with obesity in dogs. Because renal sympathetic activity is also increased in obese humans,⁴⁰ it is likely that the renal nerves also have a key role in human obesity hypertension.

Effects of 5 weeks of a high-fat diet on mean arterial pressure and cumulative sodium balance in dogs with innervated kidneys (control) and bilaterally denervated kidneys (denervated). (Redrawn from data in Kassab et al⁴⁵).

Figure 1.

Mechanisms of sympathetic activation in obesity

Although it is clear that obesity increases renal tubular sodium reabsorption, impairs renal-pressure natriuresis, and causes hypertension, in part, by increasing renal sympathetic nerve activity, the mechanisms that increase renal sympathetic activity have not been fully elucidated. Some potential mediators of sympathetic activation in obesity that we have investigated include: 1) hyperinsulinemia, 2) fatty acids, 3) angiotensin II (Ang II), 4) renal afferent nerves, and 5) hyperleptinemia.

Hyperinsulinemia does not mediate sympathetic activation and hypertension in obesity

Obesity is almost invariably associated with fasting hyperinsulinemia and exaggerated insulin responses to glucose loads.⁴⁶ The high plasma insulin concentrations are needed to maintain glucose homeostasis and to compensate for impaired metabolic effects of insulin in obesity, a condition often referred to as insulin resistance. Some tissues retain their sensitivity to insulin, however, and the elevated insulin levels have been suggested to cause hypertension through multiple effects, including sympathetic activation.¹⁶ Acute studies suggest that high insulin levels may cause modest sodium retention and increased sympathetic activity, and these observations have been extrapolated to infer that hyperinsulinemia may be an important cause of obesity hypertension through activation of the sympathetic nervous system. In fact, this concept is one of the most widely quoted mechanisms of obesity-induced sympathetic activation and hypertension.

However, neither acute nor chronic hyperinsulinemia, lasting for several weeks, has been shown to cause a hypertensive shift of pressure natriuresis or increased arterial pressure in humans and dogs.⁴⁶ In fact, insulin infusions at rates that raise plasma concentrations to levels found in obesity tend to reduce arterial pressure by causing peripheral vasodilation.⁴⁶ Insulin also did not potentiate the blood pressure or renal effects of other pressor substances such as norepinephrine or Ang II.⁴⁶ Moreover, hyperinsulinemia did not increase arterial pressure even in obese dogs that were resistant to the metabolic and vasodilator effects of insulin.⁴⁷

We also tested in dogs whether hyperinsulinemia could increase blood pressure through direct central nervous system (CNS) effects by infusing insulin for several days into the cerebral circulation; our results provided no evidence that long-term, selective CNS hyperinsulinemia causes hypertension⁴⁸(Fig. 2). Thus, multiple studies indicate that increased insulin levels may not explain sympathetic activation, increased renal tubular sodium reabsorption, shift of pressure natriuresis, or hypertension associated with obesity in dogs or in humans.

Effects of bilateral vertebral artery insulin infusion on mean arterial presure, cardiac output, and total peripheral vascular resistance in dogs. C = control; E = experimental; R = recovery. (Redrawn from data in Hildebrandt et al⁴⁸). This protocol produced a marked increase in insulin concentration in the cerebral circulation, but not in the systemic arterial plasma.

Figure 2.

In rats, long-term insulin infusion causes a small increase in arterial pressure, but this response is not related to sympathetic activation because it is unaltered by adrenergic blockade.⁴⁹ Instead, insulin-induced increases in blood pressure in rats are completely abolished by blocking the renin-angiotensin system⁵⁰ or inhibiting thromboxane synthesis,⁵¹ suggesting important interactions between these systems in mediating insulin hypertension in rats. However, the pressor response to hyperinsulinemia appears to be unique to rodents and is not observed in humans or dogs. Therefore, hyperinsulinemia cannot explain sympathetic activation and hypertension in obese dogs or humans.

Do fatty acids increase sympathetic activity and blood pressure in obesity?

High levels of fatty acids have also been postulated to raise blood pressure by increasing sympathetic activity or by enhancing the vasoconstrictor responses to sympathetic activation.^52,53 For example, increased portal venous delivery of fatty acids to the liver in subjects with visceral obesity has been suggested to activate hepatic afferent pathways that, in turn, lead to sympathetic activation.⁵³ Fasting levels of fatty acids are approximately twofold greater in obese compared with lean subjects, and acute increases in fatty acids caused by infusion of intralipid and heparin enhance vascular reactivity to α-adrenergic agonists.⁵² High levels of fatty acids also enhance reflex vasoconstrictor responses in the peripheral circulation.⁵²

Grekin et al⁵³ reported that infusions of oleic acid into the portal or systemic veins for 60 min increased blood pressure and heart rate in rats, and that these effects were abolished by adrenergic blockade. Because portal vein infusion caused a greater rise in blood pressure than did systemic infusion of oleic acid, afferent pathways originating in the liver were postulated to activate the sympathetic nervous system in response to increased levels of fatty acids.⁵³ Steinberg et al⁵⁴ also reported that high rates of intralipid and heparin infusions (which raised free fatty acid levels ninefold) in humans caused a small (<4 mm Hg) increase in mean arterial pressure.

The long-term effects of fatty acids on blood pressure regulation, however, are less clear. Grekin et al⁵³ reported that portal vein infusion of oleic acid for 7 days raised blood pressure and heart rate in rats. In contrast, we found no evidence for a long-term blood pressure response to high levels of fatty acids in dogs. We infused a mixture of long-chain fatty acids for 7 days directly into the cerebral circulation,⁵⁵ the portal vein (unpublished observations, J. E. Hall), or intravenously (IV) in chronically instrumented dogs while measuring blood pressure minute by minute, 24 h/day. In all of these experiments, we found no significant changes in arterial pressure, systemic hemodynamics, or renal function during chronic infusions of fatty acids. Also, infusion of fatty acids did not alter the chronic blood pressure response to vertebral artery Ang II infusion.⁵⁵ Although these observations provide no support for the hypothesis that fatty acids increase arterial pressure, further studies are needed to examine the role of fatty acids in linking obesity and sympathetic activation. In addition, the role of chronic increases in plasma fatty acid levels in causing hypertension through other effects besides sympathetic activation, such as vascular or renal injury, should be further considered.

Does ang II increase sympathetic activity and blood pressure in obesity?

Plasma renin activity (PRA) is significantly increased in many obese subjects despite marked sodium retention and increased extracellular fluid volume.^5,15 A role for increased levels of Ang II in stimulating sodium reabsorption and raising blood pressure in obesity is suggested by the observation that treatment with an Ang II antagonist attenuated the sodium retention, volume expansion, and increased arterial pressure in dogs fed a high-fat diet.⁵⁶ Also, angiotensin-converting enzyme (ACE) inhibition markedly reduced blood pressure in obese dogs.⁵⁷ Finally, clinical studies suggest that ACE inhibitors are effective in lowering blood pressure in young obese patients.⁵⁸

Whether these effects of Ang II in raising blood pressure in obesity are due primarily to direct actions on the kidneys or to sympathetic activation, however, is still unclear. There is considerable evidence that Ang II has direct effects on the CNS, including stimulation of thirst. However, controversy remains regarding the physiologic importance of Ang II's role in regulating sympathetic activity. This is partly due to the paucity of experiments that have examined the long-term cardiovascular and sympathetic effects of physiologic increases in CNS levels of Ang II.

The observations of Hildebrandt et al⁵⁹ are consistent with a possible effect of physiologic levels of Ang II on the CNS to raise arterial pressure. Vertebral artery infusion of Ang II at a rate of only 0.5 ng/kg/min increased arterial pressure about 11 mm Hg on the first day of infusion, and the rise in pressure was maintained at 13 mm Hg above normal after 7 days of infusion. In contrast, IV infusion of Ang II at the same dose raised arterial pressure only about 4 mm Hg on the first day. However, even this low dose of IV infused Ang II raised arterial pressure by about 13 mmHg after 7 days of infusion. Thus, physiologic levels of Ang II clearly have direct central effects that acutely (for at least 24 h) raise blood pressure. Whether these effects are important in maintaining chronic elevations in arterial pressure in obesity remains to be determined.

Renal afferent nerves do not contribute to hypertension in obesity

Intrarenal pressures are markedly elevated in obesity owing, in part, to compression of the kidneys by extrarenal adipose tissue and proliferation of extracellular matrix within the kidney which is surrounded by a capsule with low compliance.³³ Multiple studies suggest that the kidneys are richly endowed with mechanoreceptors that can activate renal afferent nerves and sympathetic activity when stimulated by short-term increases in intrarenal pressures.⁶⁰ Whether these renal sensory afferent pathways have a major role in long-term blood pressure regulation, however, is still uncertain.

To test their importance in obesity, we surgically removed renal sensory afferent fibers by dorsal root rhizotomies between T-10 and L-2 segments.⁶¹ This procedure, however, did not significantly attenuate the increased renal tubular reabsorption, sodium retention, or hypertension in dogs fed a high-fat diet.⁶¹ Thus, although the renal efferent sympathetic fibers contribute to sodium retention and hypertension in obesity, afferent pathways originating in the kidney do not appear to have a major role in raising blood pressure.

Does hyperleptinemia increase sympathetic activity in obesity?

One of the more promising possible links between obesity and sympathetic activation is hyperleptinemia. Leptin is a 167-amino acid peptide produced mainly by white adipocytes. Fasting plasma levels rise in proportion to adiposity,¹⁷ although adipocyte leptin synthesis and secretion are now recognized to be modulated by multiple factors including glucocorticoids, insulin, and β-adrenergic activity.⁶² Leptin from the plasma crosses the blood-brain barrier through a saturable transport system and acts on receptors in the lateral and medial regions of the hypothalamus to regulate energy balance by decreasing appetite and increasing energy expenditure through sympathetic stimulation (Fig. 3). Although leptin's effects on energy balance have been extensively studied, its effects on sympathetic activity and cardiovascular function are not as well understood.

Effect of bilateral carotid artery infusion of leptin at 0.1 μg/kg/min (5 days) and 1.0 μg/kg/min (7 days) on mean arterial pressure, heart rate, and daily food intake in conscious normal Sprague-Dawley rats. (Redrawn from data in Shek et al⁷⁵)

Figure 3.

Short-term effects of leptin on sympathetic activity and arterial pressure

Intravenous or intracerebroventricular (ICV) infusions of leptin increase sympathetic activity in the kidneys, adrenals, and brown adipose tissue (BAT).^20,63 The short-term effect of leptin on sympathetic activity is dose-dependent and occurs in the absence of changes in plasma insulin or glucose.²⁰ Also, the increase in sympathetic activity is slow in onset and may not be fully developed even after 2 to 3 h of leptin administration.⁶³

Despite an increase in sympathetic activity in several vascular beds, leptin administration often has little short-term effect on blood pressure,^20,63 although small increases in arterial pressure have been observed in some studies when large doses of leptin are injected into the cerebral ventricles.⁶⁴ The lack of an acute pressor effect of leptin may be due to opposing depressor effects, such as stimulation of endothelial-derived nitric oxide,⁶⁵ which offset the effects of increased sympathetic activity. Alternatively, the sympathetic stimulation caused by leptin may be too mild to cause marked peripheral vasoconstriction and transient increases in arterial pressure. However, even modest renal sympathetic stimulation could, over a period of several days, raise arterial pressure by increasing renal tubular sodium reabsorption.

Role of neuropeptide-Y (NPY) in mediating effects of leptin

Decreased NPY formation in the hypothalamus was initially believed to be the primary mediator of leptin's effects on appetite.⁶⁶ Injection of NPY into the hypothalamus evokes virtually all of the features of leptin deficiency, including hyperphagia, reduced BAT thermogenesis, and obesity.⁶⁶ NPY expression is also increased in the leptin-deficient ob/ob mouse and leptin repletion restores NPY expression to normal.⁶⁶ The ob/ob phenotype appears to be mediated, in part, by increased NPY because ob/ob mice in which NPY expression has been knocked out (NPY⁻/NPY⁻) are substantially less obese than ob/ob mice with normal NPY expression. However, obesity in these mice is severe even in the absence of NPY expression and they respond normally to the satiety effects of leptin, indicating that leptin must also act on other targets to induce satiety.⁶⁶

Central administration of NPY into the nucleus tractus solitarius or caudal ventrolateral medulla reduces blood pressure.⁶⁷ Because leptin reduces NPY expression in the hypothalamus, decreased NPY levels associated with hyperleptinemia could conceivably contribute to the hypertensive effects of leptin. However, this hypothesis has not, to our knowledge, been directly tested. Currently, there is little information on the role of decreased CNS levels of NPY in mediating the short- or long-term effects of leptin on sympathetic activity and arterial pressure.

Role of melanocortin-4 receptors (MC4-R) in mediating effects of leptin

The proopiomelanocortin (POMC) pathway may interact with leptin to stimulate sympathetic activity and to regulate energy balance. Targeted deletion of the MC4-R induces obesity in rodents⁶⁸ and central administration of MC4-R agonists decreases feeding.⁶⁹ The endogenous ligand for the MC4-R appears to be melanocyte-stimulating hormone (α-MSH) produced from POMC precursors. Leptin increases expression of POMC in the arcuate nucleus⁷⁰ and it is possible that this effect could be part of a feedback pathway for control of appetite and sympathetic activity. Increasing leptin, associated with obesity, would stimulate arcuate POMC expression and α-MSH, which would then act elsewhere in the hypothalamus on MC4-R-expressing neurons, causing decreased food intake and increased sympathetic activity. The MC4-R pathway, however, is not restricted to a single ligand, but also responds to other substances, such as the agouti protein, which acts as an antagonist on this receptor. Yellow agouti mice, which have ectopic overexpression of agouti peptide, are obese and hyperleptinemic owing to antagonism of the hypothalamic melanocortin system by the excess agouti protein.⁶⁹

Short-term studies suggest that the MC4-R may be important in mediating leptin's effects on appetite and sympathetic activity. Treatment of rodents with an MC4-R antagonist attenuated the transient satiety-inducing action of leptin⁶⁹ and completely abolished the increased renal sympathetic activity associated with short-term ICV leptin infusion in rats.⁷¹ Surprisingly, MC4-R blockade did not prevent leptin-induced stimulation of sympathetic activity in BAT.⁷¹ This finding suggests that the thermogenic effects of leptin in BAT are not mediated through the MC4-R, whereas the short-term effect of leptin to enhance renal sympathetic activity appears to depend on an intact MC4-R. These differing effects of MC4-R blockade on BAT and renal sympathetic activity also suggest that leptin may activate the sympathetic nervous system through multiple central pathways.

Administration of an MC4-R antagonist in mice has been reported to increase food intake but to have no effect on blood pressure for up to 8 h.⁷² However, the physiologic role of the melanocortin system in mediating the long-term effects of leptin on sympathetic activity and arterial pressure, especially in humans, remains to be determined.

Interactions of leptin with other neurochemicals in the hypothalamus

Recent studies suggest that the lateral hypothalamus releases an array of neurochemicals, including the orexins and melanin-concentrating hormone (MCH), that regulate appetite and energy homeostasis.⁶⁶ Some of these have been shown, at least in short-term experiments, to influence blood pressure. For example, ICV injections of orexins increased renal sympathetic activity, heart rate, and arterial pressure in rats.⁷³ However, hypothalamic expression of the orexins usually increases with starvation and decreases with increased energy intake.⁷⁴ Therefore, orexin levels are reduced in situations when leptin is increased (eg, obesity) and therefore probably do not mediate the hypertensive effects of leptin. However, the importance of orexins and other neurochemical pathways in the hypothalamus in modulating the chronic effects of leptin on sympathetic activity, thermogenesis, and arterial pressure are largely unexplored.

Leptin and long-term control of arterial pressure

Although leptin has both pressor and depressor actions, and short-term leptin administration has little net effect on arterial pressure, long-term infusion of leptin raises blood pressure in rodents. In nonobese Sprague-Dawley rats, IV or intracarotid artery infusion of leptin for 12 days, at rates that raise plasma concentration to levels (90 to 95 ng/mL) similar to those found in severe obesity, significantly increased mean arterial pressure and heart rate, measured 24 h/day using computerized methods (Fig. 4).⁷⁵ The rise in arterial pressure was slow in onset and occurred despite a reduction in food intake that would tend to reduce arterial pressure. Aizawa-Abe et al⁷² found that transgenic skinny mice in which leptin is secreted ectopically by the liver in large amounts also develop mild hypertension⁷² comparable to that produced by long-term leptin infusions.⁷⁵ Agouti mice, which are obese and have high levels of circulating leptin, are also hypertensive despite antagonism of the hypothalamic melanocortin receptors by the high levels of agouti protein in the mice.^18,72 This suggests that leptin-induced hypertension may be at least partly independent of stimulation the melanocortin system.

Possible links among leptin and its effects on the hypothalmus, sympathetic activation, and hypertension. Leptin may mediate some of its effects on appetite and sympathetic activity by inhibiting (−) or stimulating (+) other neurochemical pathways, including α-melanocyte-stimulating hormone, melanin concentrating hormone (MCH), agouti-related peptide (AGRP), and neuropeptide Y (NPY).

Figure 4.

The mechanisms by which increased circulating leptin chronically raises arterial pressure and heart rate are not entirely clear, but are consistent with activation of the sympathetic nervous system. We have demonstrated that combined α- and β-adrenergic blockade completely abolished the usual increases in arterial pressure and heart rate during 14 days of leptin infusion.⁷⁶ In fact, after α- and β-adrenergic blockade, long-term leptin infusion reduced arterial pressure and heart rate, possibly owing to decreased food intake and weight loss.⁷⁶ Combined α- and β-adrenergic blockade, however, did not attenuate leptin-induced reductions in food intake or decreases in insulin and glucose levels. Also, administration of adrenergic or ganglionic blockers normalized blood pressure in transgenic skinny mice with leptin-induced hypertension.⁷² These observations indicate that increased adrenergic activity is essential for leptin-induced hypertension and tachycardia but does not have a major role in mediating the effects of leptin on insulin secretion or glucose homeostasis in nonobese rats.

Does “leptin resistance” attenuate leptin's actions on sympathetic activity and arterial pressure in obesity?

The finding that increasing plasma leptin raises arterial pressure in nonobese rats is consistent with the possibility that leptin may be an important link between obesity, sympathetic activity, and hypertension. However, if obesity is associated with resistance to the effects of leptin on the hypothalamus, and therefore resistance to the effects of leptin on satiety and sympathetic activity, elevated leptin concentrations might cause minimal stimulation of sympathetic activity in obese subjects (Fig. 5).

Possible interactions among leptin, sympathetic activity, endothelial dysfunction, and leptin resistance in increasing renal tubular sodium reabsorption and mediating obesity hypertension. The net effect of leptin on blood pressure would depend on the degree of resistance to the sympathoexcitatory effects and the degree of endothelial dysfunction.

Figure 5.

The fact that most obese human subjects have high circulating leptin and continue to overeat has been interpreted as evidence for leptin resistance. In addition, some rodent models of obesity have a reduced responsiveness to leptin's anorexic effects.⁷⁷ In some instances, such as in the Zucker fatty rat, the leptin resistance is caused by an abnormality of the leptin receptor.⁷⁸ However, in dietary-induced obesity there is little evidence for defective leptin receptor function. Diminished responsiveness to exogenous leptin in obese subjects is consistent with at least three possibilities: 1) obese subjects are resistant to the effects of leptin on the hypothalamus, through receptor or postreceptor signaling defects; 2) there is a saturation of the transporter for leptin across the blood-brain barrier in some subjects; or 3) other factors override the long-term effects of leptin on the hypothalamus in obese subjects. There is some support for each of these possibilities. For example, diet-induced obesity in rodents is associated with impaired transport of leptin across the blood-brain barrier, and mice fed a high-fat diet exhibit resistance to the satiety effects of centrally, but not peripherally, administered leptin.⁷⁹ Also, transient ICV leptin administration increased lumbar sympathetic activity in nonobese rats, but had minimal effects in obese rats fed a high-fat diet.⁸⁰

These observations are consistent with the hypothesis that obesity induces resistance to the short-term effects of leptin on sympathetic activity. However, another explanation is that basal sympathetic activity is already elevated in obese rats, owing to high circulating leptin, and therefore further increases in leptin (above pathophysiologic levels) may not cause greater sympathetic stimulation. Also, renal (rather than muscle) sympathetic nerves mediate the long-term effects of sympathetic activation to raise blood pressure in obesity.⁴⁵ Whether diet-induced obesity attenuates the renal sympathetic responses to leptin is unknown. Nor have the long-term effects of leptin on blood pressure and heart rate been studied in obese compared with lean subjects. Thus, a major issue that remains unresolved is whether there is resistance to the effects of leptin to renal sympathetic activity and whether leptin contributes to increased blood pressure in obese subjects.

Does endothelial dysfunction amplify the hypertensive effect of leptin?

Functional leptin receptors are expressed in vascular endothelial cells and leptin induces nitric oxide (NO)-mediated vasorelaxation in vitro. Fruhbeck et al⁸¹ demonstrated that infusion of leptin increased serum NO concentrations and that after inhibition of NO synthesis, acute leptin infusions significantly increased arterial pressure, suggesting that increased NO synthesis may oppose the hypertensive effects of leptin-induced sympathetic stimulation. We have recently shown that inhibition of NO synthesis mildly enhances the chronic renal hemodynamic and hypertensive effects of leptin, but markedly amplifies the tachycardia caused by hyperleptinemia in rats.⁸²

To the extent that obesity causes endothelial dysfunction and impaired NO release, one might expect greater blood pressure responses to hyperleptinemia in obese compared with lean subjects (Fig. 5). Thus, the net effect of leptin on blood pressure in obesity depends on: 1) the degree of resistance in the hypothalamus to the sympathoexcitatory effects of leptin, and 2) the degree on endothelial dysfunction. Currently, there are no studies directly assessing the importance of these factors in modulating leptin's long-term effects on control of blood pressure in obesity.

Leptin and human essential hypertension

Because obesity has a major role in contributing to human essential hypertension, it is not surprising that plasma leptin concentrations are elevated in hypertensive patients, or that leptin and blood pressure are correlated. Hirose et al⁸³ found that serum leptin levels were highly correlated with mean arterial pressure and BMI in male Japanese adolescents. Moreover, heart rate was also correlated with serum leptin even after adjustment for age and BMI. Suter et al⁸⁴ also found that systolic blood pressure correlated with plasma leptin after adjustment for BMI in women and in nonhypertensive men, but not in hypertensive men. Most of the data suggest that the correlation between leptin and blood pressure in hypertensive men is related mainly to the correlation between adiposity and blood pressure.

Not all studies, however, have shown a close relationship between leptin and hypertension. For example, genetic markers at the leptin locus are not significantly linked to hypertension in African Americans.⁸⁵ This finding does not imply that leptin is unimportant in mediating obesity hypertension in African Americans, but merely that genetic abnormalities of leptin expression are not associated with essential hypertension. This is perhaps not surprising as there are few obese people with a genetic deficiency of leptin production.

The complexity of the relationships between leptin and long-term blood pressure regulation is further illustrated by the finding that lower body obesity causes greater increases in leptin than visceral obesity, even though visceral obesity is more closely associated with hypertension. Also, leptin levels are greater in women than men when compared at the same BMI, even though blood pressure is slightly higher in men. These observations, at the very least, indicate that other factors besides leptin contribute to obesity hypertension. However, the multiple interactions of leptin with other neurochemicals in the hypothalamus, as well as the peripheral metabolic, cardiovascular, and renal actions of leptin, are just beginning to be investigated and will require additional long-term studies before their significance in human obesity and its cardiovascular consequences can be fully appreciated.

Activation of the sympathetic nervous system is, however, only one of the mechanisms by which obesity elevates blood pressure. The renin-angiotensin system as well as physical compression of the kidney may also be important factors in raising blood pressure in obesity.^23,36 In view of the fact that obesity accounts for 65% to 75% of human essential hypertension, it is clear that unraveling the mechanisms by which weight gain increases sympathetic activity, alters renal function, and raises blood pressure will provide the key to understanding human essential hypertension.

Author notes

*

The authors’ research was supported by a grant from the National Heart, Lung, and Blood Institute (grant P01HL51971).

© American Journal of Hypertension, Ltd. 2001