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. Author manuscript; available in PMC: 2009 Sep 17.
Published in final edited form as: Circulation. 2008 Jun 24;117(25):3238–3249. doi: 10.1161/CIRCULATIONAHA.107.741645

Leptin and Cardiovascular Disease

Response to Therapeutic Interventions

Kwang Kon Koh 1, Sang Min Park 1, Michael J Quon 1
PMCID: PMC2746068  NIHMSID: NIHMS105021  PMID: 18574061

Leptin, a 16-kDa hormone identified and cloned in 1994, is synthesized and secreted specifically from white adipose cells.1 Leptin has a variety of important central and peripheral actions to regulate energy balance and metabolism, fertility, and bone metabolism that are mediated by specific cell surface leptin receptors.2,3 Importantly, leptin may also exert actions related to cardiovascular homeostasis that are potentially atherogenic, thrombotic, and angiogenic.4-6 Leptin has peripheral actions to stimulate vascular inflammation, oxidative stress, and vascular smooth muscle hypertrophy that may contribute to pathogenesis of type 2 diabetes mellitus, hypertension, atherosclerosis, and coronary heart disease.3,4,7

Insulin resistance,8 systemic hypertension, and hypercholesterolemia9 all contribute independently to vascular endothelial dysfunction that promotes atherosclerosis and coronary heart disease. Reciprocal relationships between endothelial dysfunction and insulin resistance are characterized by impaired insulin-stimulated nitric oxide (NO) production from endothelium that decreases blood flow to insulin target tissues.10,11 Relationships among obesity, metabolic syndrome, diabetes mellitus, and their cardiovascular complications are well established. However, the mechanisms by which excess adiposity causes both insulin resistance and vascular dysfunction are not well understood. Direct vascular effects of adipokines such as leptin are attractive candidates that may help to explain underlying pathophysiological mechanisms.

Several clinical studies demonstrate that hyperleptinemia predicts acute cardiovascular events, restenosis after coronary injury such as angioplasty, and cerebral stroke independent of traditional risk factors.12-14 Leptin-deficient hyperlipidemic mice (ob/ob; apolipoprotein E [apoE]-/- mice) develop significantly less atherosclerosis than apoE-/- mice on an atherogenic diet. Exogenous leptin significantly increases atherosclerotic areas in apoE-/- mice. Taken together, these findings support the notion that leptin accelerates atherosclerosis.15

By contrast, some data indicate that leptin may protect against atherosclerosis in specific animal models. For example, low-density lipoprotein-receptor knockout mice lacking leptin (LDLR-/- ob/ob) develop more atherosclerotic lesions than LDLR-/- control mice.16 Moreover, in 207 women with normal glucose tolerance, impaired glucose tolerance, or type 2 diabetes mellitus, low plasma leptin predicted cardiovascular mortality during a 7-year follow-up period.17 Thus, the net effects of leptin on cardiovascular pathophysiology are complex and not completely understood.

In this review, we discuss cardiovascular actions of leptin related to atherosclerosis, insulin resistance, and hypertension. Particular emphasis is given to insights derived from therapeutic interventions with lifestyle modification, cardiovascular drugs, antidiabetic drugs, and other related treatments.

Biology and Metabolism of Leptin

The adipocyte is an active endocrine secretory cell releasing free fatty acids and several cytokines and hormones including leptin, adiponectin, tumor necrosis factor-α, and angiotensin II (Ang II).18 Leptin is primarily involved in central regulation of food intake and energy expenditure. Leptin was identified by positional cloning of the ob gene, which determines obesity in ob/ob mice.1 Leptin may participate in several mechanisms of disease associated with obesity. It acts on a specific receptor located in the hypothalamus to decrease appetite and increase energy expenditure. Thus, adipose cell-derived leptin functions as the afferent component of a negative feedback loop that helps to maintain stable adipose tissue mass.2,3 Leptin acts on target cells through plasma membrane receptors (6 isoforms, Ob-Ra through Ob-Rf). Ob-Rb, known as the “long” isoform, is highly expressed in hypothalamus and mediates the anorectic effect of leptin. Other receptor isoforms such as Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf (“short” isoform) are expressed in peripheral tissues.

Leptin Resistance

In obesity, elevated leptin levels are not sufficient to prevent dysregulation of energy balance, suggesting that obese people are leptin resistant.3 Although most cases of human obesity are associated with hypothalamic leptin resistance, little is known about the peripheral effects of leptin in obese individuals. According to the concept of selective leptin resistance,19 only the anorectic effect of leptin is impaired, whereas its other activities are maintained in obese subjects. Because many potentially proatherogenic effects of leptin have been described, hyperleptinemia may contribute to atherogenesis in obese individuals. The observation that leptin-deficient ob/ob mice are protected from arterial thrombosis or neointimal hyperplasia induced by arterial injury is consistent with this hypothesis.4 An alternative possibility is that hyperleptinemia is not causally linked to atherogenesis but only reflects the state of leptin resistance. Moreover, leptin resistance rather than hyperleptinemia may also contribute to atherosclerosis because of impairment of the beneficial effects of leptin.4

The mechanisms underlying leptin resistance are still being defined. In human blood, several serum leptin-interacting proteins have been isolated, including C-reactive protein (CRP). Human CRP directly inhibits binding of leptin to its receptors and blocks its ability to signal in cultured cells. In vivo, infusion of human CRP into ob/ob mice impairs the ability of leptin to promote satiety and weight reduction. In mice that express a transgene encoding human CRP, the actions of human leptin are blunted.20

In addition to acquired leptin resistance in obesity, leptin resistance may also be determined by genetic factors. For example, db/db mice bear a missense mutation within the leptin receptor gene. Obese Zucker fatty rats and fa/fa mice have an amino acid substitution within the extracellular portion of the leptin receptor, resulting in reduced affinity for leptin. Rare examples exist of human leptin and leptin receptor mutations causing monogenic forms of obesity.21

Atherogenic Effects of Leptin

Leptin and Endothelial Cells

Functional leptin receptors are present on endothelial cells. However, the actions of leptin to modulate endothelial function remain controversial. In vitro studies demonstrate that leptin at high concentrations elicits endothelium-dependent NO-mediated vasorelaxation in rats.22 In addition, leptin may upregulate inducible NO synthase to generate large amounts of NO that impair endothelial function and promote atherogenesis by inducing oxidative stress.23 When it is exposed to free radicals generated from oxidative stress, NO may undergo conversion to toxic molecules such as peroxynitrite that impair endothelial function.9,23,24 Leptin at pathophysiologically relevant “obese-range” concentrations (but not at low physiological concentrations) impairs NO-dependent vasorelaxation induced by acetylcholine both in vitro and in vivo.25

Several human studies suggest that leptin contributes to endothelial dysfunction or damage in some pathological states.15,26-28 By contrast, no correlation between leptin and endothelial function is observed in healthy adolescents29 and hypertensive patients.30 Thus, the role of leptin in regulating endothelial function in humans remains controversial and may depend on the context of cardiovascular pathophysiology that is present or absent.

Leptin and Lipid Profile

Leptin stimulates lipoprotein lipase secretion in cultured human and murine macrophages.31 Leptin increases accumulation of cholesterol esters in foam cells, especially at high glucose concentrations.32 However, under normoglycemic conditions leptin may protect macrophages from cholesterol overload.33 Several studies demonstrate an inverse relationship between leptin and high-density lipoprotein (HDL) cholesterol and/or apolipoprotein A-I in humans.34 Leptin promotes hepatic HDL clearance by upregulating scavenger receptor type B1 and decreases plasma HDL level in mice.35 Thus, in the context of hyperglycemia, leptin may impair cholesterol removal from peripheral tissues by lowering HDL and unfavorably affect local cholesterol balance in diabetic patients.

Leptin and Inflammatory Markers

Leptin potentiates secretion of tumor necrosis factor and interleukins 2 and 6,36 increases generation and accumulation of reactive oxygen species, and enhances expression of monocyte chemoattractant protein-1.37 Leptin stimulates production of proinflammatory cytokines and enhances production of Th1-type cytokines.38 In endothelial cells, leptin stimulates transforming growth factor-β synthesis.39

Physiological concentrations of leptin stimulate expression of CRP in primary human hepatocytes.20 We observed correlations between plasma leptin and plasma CRP levels.28 However, this was not observed in another study30 in patients with hypertension. Thus, the ability of leptin to promote proinflammatory signaling through cytokines and growth factors may contribute to endothelial dysfunction, atherosclerosis, and insulin resistance in hyperleptinemic states.

Leptin and Smooth Muscle Cells

Leptin stimulates migration and proliferation of vascular smooth muscle cells and expression of matrix metalloproteinase-2 in human aorta in vitro.40 Interestingly, stretching the vascular wall induces expression of both leptin and its receptor in rabbit portal vein.41 Leptin stimulates synthesis and secretion of endothelin-1 in human umbilical vein endothelial cells42 and expression of preproendothelin-1 and endothelin ETA receptor genes, angiotensinogen, and angiotensin type 1 receptor expression in rabbit portal vein smooth muscle cells.41 Finally, leptin stimulates osteoblastic differentiation and hydroxyappatite production by calcifying vascular smooth muscle cells.43

Leptin and Reactive Oxidative Stress

Ob/ob mice are characterized by impaired antioxidant defense, as evidenced by reduced activity of catalase, glutathione peroxidase, and glutathione reductase. Leptin therapy corrects these abnormalities.44 Leptin may increase oxidative stress through multiple mechanisms. In bovine aortic endothelial cells, leptin increases formation of reactive oxygen species in a process coupled with increased fatty acid oxidation and activation of protein kinase A.37 In rats, chronic induction of hyperleptinemia decreases paraoxonase 1 activity. This is followed by increased plasma and urinary concentration of isoprostanes.45 Leptin treatment is also associated with increases in other lipid peroxidation products such as malondialdehyde and 4-hydroxyalkenals in renal tissue.

Leptin increases NADPH oxidase expression and activity in isolated murine cardiomyocytes. This effect is attenuated by endothelin receptor antagonists.46 Paraoxonase 1 activity is decreased in obese women compared with normal-weight controls and inversely correlates with plasma leptin.47 Thus, in hyperleptinemic states such as obesity, leptin may increase oxidative stress through multiple mechanisms.

Leptin and Thrombosis

Leptin increases expression of P-selectin on human platelets in vitro.48 Interestingly, enhancement of the effects of leptin on ADP-induced aggregation is attenuated in platelets obtained from overweight or obese individuals compared with normal-weight subjects.49 However, in other studies, no effect of leptin is observed at concentrations up to 500 ng/mL from normal-weight or obese subjects.50

In 44 obese women, plasma leptin significantly correlates with urinary excretion of 11-dehydrothromboxane B2.51 Caloric restriction reduces leptin levels and is associated with reduced platelet activity. This is reflected by decreased plasma concentration of P-selectin. In men with ischemic heart disease, leptin also positively correlates with the plasma concentration of plasminogen activator inhibitor-1.52 In the Health Professionals Follow-up Study, leptin significantly correlates with fibrinogen and von Willebrand factor.53 In a Swedish population-based study, leptin positively correlates with plasma fibrinogen and inversely correlates with tissue plasminogen activator concentration in plasma.54 An inverse relationship between leptin and 2 inhibitors of coagulation, protein C and tissue factor pathway inhibitor, is also noted in patients with end-stage renal disease.55 Taken together, these data suggest that in some contexts leptin may contribute to platelet hyperactivity and a pathological shift in the coagulation-fibrinolysis balance observed in the metabolic syndrome.

Leptin and Ang II

Ang II increases leptin synthesis in cultured adipose cells56 and in rats in vivo.57 Adipose tissue-derived Ang II and leptin may act synergistically to promote obesity-related hypertension. This hypothesis is supported by epidemiological observations demonstrating that plasma renin activity, serum angiotensinogen, and leptin levels are strongly correlated in lean and obese normotensive and hypertensive subjects.58,59 Ang II also potentiates sympathetic nervous system activity. Given that leptin increases sympathetic activity,60 obese subjects with activation of the renin-angiotensin system may have enhanced sympathetically mediated vasoconstriction in response to leptin. Differential effects of local versus systemic Ang II are observed in the regulation of leptin release from rat adipocytes. Incubation of adipocytes with Ang II results in increased leptin mRNA expression and leptin release. Basal and Ang II-stimulated release of leptin from isolated adipocytes is initially increased; thereafter, leptin release declines to levels less than those of control. Infusion of Ang II increases catecholamine turnover in adipose tissue. Moreover, sympathetic blockade eliminates differences in plasma leptin concentration between saline- and Ang II-infused rats.57 Thus, locally produced Ang II may directly increase leptin secretion from adipocytes. However, with systemic elevations in Ang II, sympathetic activation may counterbalance effects from locally produced Ang II.

Leptin and Insulin

Insulin potentiates leptin-induced NO release by enhancing leptin-stimulated phosphorylation of Akt and endothelial NO synthase. This raises the possibility of cross talk between insulin and leptin signaling.61 By contrast, leptin does not alter mesenteric blood flow in conscious rats treated with NO synthase inhibitors or α-adrenergic blockers, despite increased sympathetic activity.62 These results suggest that leptin alters the NO-dependent vascular reactivity of resistance vessels. Intriguingly, systemic leptin administration does not attenuate vasoconstriction caused by sympathetic nerve stimulation, suggesting that direct vasodilator actions of leptin may be insufficient to oppose sympathetically mediated vasoconstriction.63 Thus, although leptin may possess beneficial NO-dependent vasodilator actions, the net effects of leptin on vascular function in vivo are still unclear and may depend on the presence or absence of other metabolic and cardiovascular pathophysiology.5

Leptin increases insulin sensitivity in rats and may improve vascular responses to insulin in states of insulin resistance.64 Leptin secretion by adipocytes is stimulated by insulin, and plasma leptin significantly correlates with plasma insulin.65 By contrast, under some conditions, leptin negatively regulates insulin signaling66 and glucose uptake.67

Leptin increases free fatty acid oxidation in isolated mouse soleus muscle by 42%, whereas insulin decreases this by 40%. When both hormones are administered, leptin attenuates both the antioxidative and lipogenic effects of insulin by 50%.68 Leptin attenuates the antioxidative, lipogenic actions of insulin on muscle free fatty acid metabolism via a peripheral mechanism, whereas the effects of leptin in modulating insulin-stimulated glucose disposal appear to occur via a central mechanism.2 Recombinant mouse leptin inhibits glycogen synthesis in soleus muscle of ob/ob mice in the presence of insulin.69 By contrast, leptin increases glycogen synthesis in cultured C2C12 muscle cells.70

Important peripheral actions of leptin include inhibition of insulin biosynthesis and secretion in pancreatic β-cells. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop, the so-called adipoinsular axis. Multiple signal transduction pathways are involved in leptin signaling in pancreatic β-cells. In most overweight individuals, physiological regulation of body weight by leptin seems to be disturbed, representing “leptin resistance.” This leptin resistance at the level of the pancreatic β-cell may contribute to dysregulation of the adipoinsular axis and contribute to development of hyperinsulinemia and manifest type 2 diabetes mellitus in overweight patients.3

Leptin may potentiate pressor effects of hyperinsulinemia in insulin-resistant states. Therefore, interactions between Ang II and insulin with leptin may have deleterious cardiovascular effects in the setting of obesity.

Leptin and Hypertension

Leptin administered short term has no net effect on blood pressure under healthy conditions. In lean animals, leptin activates the sympathetic nervous system. However, this is balanced by NO-dependent vasorelaxation and natriuresis so that blood pressure does not change. By contrast, chronic hyperleptinemia increases blood pressure because acute depressor effects are impaired and/or additional sympathetic nervous system-independent pressor effects appear, such as oxidative stress, NO deficiency, enhanced renal Na+,K+-ATPase activity, and Na+ reabsorption and overproduction of endothelin.7,60,71 Indeed, in obese animals, the effects of leptin on NO and natriuresis are impaired.7 Chronic leptin-dependent increases in sympathetic nervous activity and arterial pressure are mediated through increases in central nervous system corticotrophin-releasing factor activity.72

Although a cause-and-effect relationship between leptin and high blood pressure in humans has not been demonstrated directly, many clinical studies have shown elevated plasma leptin in patients with essential hypertension. In addition, a significant positive correlation exists between leptin and blood pressure independent of body adiposity in both normotensive and hypertensive individuals.73 Correlations between leptin and blood pressure are influenced by gender. Despite higher serum leptin levels in women, leptin and blood pressure associations have been reported more frequently in men than in women, regardless of hypertension and adiposity.74 Ethnic and racial background may also influence the relationship between leptin and blood pressure. We did not observe significant correlations between plasma leptin levels and blood pressure before efonidipine therapy.29

Results From Clinical Surveys

Plasma leptin is higher in male patients who subsequently develop first-ever myocardial infarction than in control subjects.75 Leptin is also an independent predictor of myocardial infarction in men and especially women with arterial hypertension.76 Plasma leptin is higher in offspring with paternal history of premature myocardial infarction than in those without family history of cardiovascular events.77 Elevated plasma leptin predicts coronary events in men during a 5-year follow-up period.12 Plasma leptin is higher in patients who subsequently develop restenosis after coronary angioplasty than in those who do not.13 Leptin is an independent predictor of hemorhagic stroke in men and women14 and of stroke (ischemic and hemorrhagic stroke) in men but not in women.78 Furthermore, leptin is a predictor of myocardial infarction, coronary events, and stroke independent of body mass index (BMI).12,14,75,76,78 Significant correlations between leptin and intima-media thickness of the common carotid artery are present in obese individuals without diabetes mellitus.79 Brachial artery distention during systolic pulse wave inversely correlates with plasma leptin in healthy adolescents.80

By contrast, no correlation between leptin and intimamedia thickness is noted in 403 elderly men without ischemic heart disease81 or in children with obesity or type 1 diabetes mellitus.82 Furthermore, leptin does not predict ischemic heart disease in men.83 It is not clear why leptin levels are correlated with preclinical atherosclerosis in some studies but not others. This may depend on the pathophysiological context of the patients studied, medications taken, or other factors.

Leptin is an independent predictor of diabetes mellitus in some studies. In Japanese Americans followed for 5 to 6 years, increased baseline leptin levels are associated with increased risk of developing diabetes mellitus in men but not in women.84 Leptin predicts development of diabetes mellitus in Mauritian men but not women in a population-based study.85 In a prospective study of nondiabetic white men with 5 years of follow-up, higher leptin levels are associated with increased risk of type 2 diabetes mellitus.86 In a population-based study of white subjects, leptin concentrations are 4 times higher in women than in men. BMI, waist circumference, insulin, and triglyceride concentrations are independently and significantly associated with leptin.87 Interestingly, low plasma leptin levels predict cardiovascular mortality.17 This may reflect the fact that both very high and very low BMI values predict increased mortality.

Leptin levels in healthy women are substantially higher than in healthy men. The mechanisms underlying these differences are unknown. Leptin signaling may differ between genders. Women have significantly higher fasting leptin, heart rate, and cardiac sympathetic activity and lower insulin sensitivity. Men show inverse correlations between insulin resistance and heart rate and between insulin resistance and cardiac sympathovagal ratio. Women, by contrast, show no sympathetic activity relationship with insulin resistance but rather an inverse correlation between leptin and the sympathovagal ratio. This suggests that leptin in women is associated with sympathetic activity.88 Spontaneous leptin secretion over 24-hour and 48-hour periods shows a gender-based difference that is significantly higher in women than in men.89 These observations may help to explain the differences in leptin concentrations between men and women.

Therapeutic Interventions

Therapeutic interventions targeting the “leptin system” may potentially prevent or reduce cardiovascular complications. Clinical studies, including some prospective trials, suggest that high plasma leptin levels are associated with development of atherosclerosis and its complications. However, the question of whether hyperleptinemia directly promotes atherosclerosis in obese subjects is still unresolved. Indeed, all evidence currently available is circumstantial, associative, and sometimes contradictory. It seems that the most convincing evidence of the proatherogenic effects of leptin is obtained by examining manipulations that reduce leptin signaling in hyperleptinemic obese animals.

Lifestyle Modifications

Leptin levels decrease after initiation of a diet to induce weight loss90 or weight loss programs.27,91 One major reason for the long-term failure of these therapies is the fact that weight-reduced obese and overweight individuals develop inappropriate hunger and are leptin resistant. The relationship between a fish diet or a vegetarian diet and leptin in Africans was examined. In both men and women, fish consumption is associated with lower plasma leptin levels than are vegetable diets.92

Recombinant Human Leptin

Patients with lipodystrophies develop severe insulin resistance, fatty liver, and hypertriglyceridemia as a result of excess fat being deposited in liver and muscle tissue. Because of reduced fat tissue, leptin levels are low. Leptin treatment is beneficial in these cases.93 Leptin therapy is also beneficial in rare cases of monogenic forms of human obesity caused by leptin mutations.21

Drugs

Renin-Angiotensin System Blocking Agents

Plasma leptin levels strongly correlate with plasma renin activity in patients with essential hypertension.94 Ang II type 1 receptor blocker treatment significantly decreases mass of both subcutaneous and mesenteric adipose tissue, improves insulin resistance, and reduces plasma leptin and leptin mRNA in adipose tissue.95 Improvement of insulin resistance by Ang II type 1 receptor blockers may be attributed, in part, to reduction of adipose tissue. Losartan treatment has no significant effect on leptin concentrations in patients with hypertension.96 In patients with mild or moderate hypertension, perindopril or felodipine does not decrease leptin and insulin levels. However, pindolol markedly suppresses leptin levels without influencing insulin levels.97 In obese patients with mild to moderate essential hypertension, felodipine has no effect on plasma leptin and insulin sensitivity. However, valsartan significantly reduces plasma leptin, insulin resistance, and BMI.98 We compared the effects of ramipril, candesartan, and ramipril combined with candesartan in 34 patients with hypertension.30 Ramipril and candesartan therapies decrease plasma leptin levels relative to respective baseline measurements by 11% and 5%, respectively. Combination therapy decreases plasma leptin levels relative to respective baseline measurements by 21%, and the magnitude of reduction with combination therapy is greater than either ramipril or candesartan monotherapy (Figure 1) despite no change in BMI after therapies. In another study, we compared effects of placebo, atenolol 100 mg, amlodipine 10 mg, hydrochlorothiazide 50 mg, ramipril 10 mg, or candesartan 16 mg in 31 patients with hypertension.99 Ramipril, candesartan, and amlodipine therapies significantly decrease plasma leptin levels relative to respective baseline measurements by 16%, 12%, and 12%, respectively. Atenolol therapy increases plasma leptin levels relative to respective baseline measurements by 15%. Thiazide therapy does not change leptin levels. Ramipril, candesartan, and amlodipine therapies significantly decrease leptin levels more than atenolol or thiazide therapies (Figure 2) despite no change in BMI after therapies.

Figure 1.

Figure 1

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Percentage change in leptin levels from respective pretreatment values after treatment with ramipril alone, combined therapy, and candesartan alone (P=0.042 by ANOVA).30 SEM is identified by bars.

Figure 2.

Figure 2

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Ramipril, candesartan, and amlodipine therapies significantly decrease leptin levels to a greater extent than atenolol or thiazide therapies.99 Pl indicates placebo; At, atenolol; Am, amlodipine; Th, thiazide; Ra, ramipril; and Ca, candesartan. *P<0.05, **P<0.01. SEM is identified by bars.

Calcium Channel Blockers

We observe significant correlations between baseline BMI and baseline leptin levels in patients with hypertension.28 In this study, efonidipine treatment also significantly decreases plasma leptin by 12%. Correlations are noted between percent changes in flow-mediated dilation and leptin levels (r=-0.467, P=0.003) and between percent changes in plasma levels of malondialdehyde and percent changes in plasma levels of leptin (r=0.364, P=0.025) after efonidipine therapy. Significant correlations exist between pretreatment insulin levels and pretreatment leptin levels (r=0.514, P<0.001) and between percentage changes in insulin levels and percentage changes in leptin levels (r=0.409, P=0.011) after efonidipine therapy. Significant inverse correlations exist between pretreatment plasma leptin levels and pretreatment insulin sensitivity index (Quantitative Insulin-Sensitivity Check Index [QUICKI]) (r=-0.431, P=0.007) and between percent changes in plasma leptin levels and percent changes in QUICKI (r=-0.400, P=0.013; Figure 3) after efonidipine therapy.

Figure 3.

Figure 3

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Scatterplots show significant inverse correlations between pretreatment plasma leptin levels and pretreatment QUICKI (r=-0.431, P=0.007) and between percent changes in plasma leptin levels and percent changes in QUICKI (r=-0.400, P=0.013) after efonidipine therapy.28 The line represents the best-fit linear regression.

β-Blockers

Atenolol therapy increases plasma leptin levels.99 Pindolol has a marked suppressive effect on leptin levels.97 The effects of other drugs in this class on leptin have not yet been investigated.

Thiazides

Thiazide therapy does not significantly change plasma leptin levels.99

Statins

Atorvastatin dose-dependently inhibits leptin secretion and mRNA expression in cultured adipocytes.100 However, pravastatin in healthy human volunteers does not change leptin levels.101 In nondiabetic patients, lovastatin and gemfibrozil do not affect serum leptin concentration, whereas lovastatin adversely affects insulin sensitivity.102

Peroxisome Proliferator-Activated Receptor Agonists

Treatment of rats with the peroxisome proliferator-activated receptor-α activator fenofibrate does not change adipose tissue and body weight and has no significant effect on leptin mRNA levels. Thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes.103 Rosiglitazone and gemfibrozil decrease serum glucose, insulin, and leptin levels in diet-induced obese rats.104 Peroxisome proliferator-activated receptor-α activation significantly decreases serum leptin levels in obese diabetic mice, whereas rosiglitazone does not.105

α1-Receptor Blockers

Bunazosin hydrochloride reduces plasma leptin levels and improves insulin resistance in hypertensive patients with obesity and hyperleptinemia.106

Metformin

Metformin effectively reduces fasting insulin and leptin in 31 morbidly obese, nondiabetic subjects with BMI >30.107

Dopamine D2 Receptor Agonist

Activation of dopamine D2 receptors by bromocriptine lowers circulating leptin levels in obese women.108

Glucocorticoid

Adipocyte leptin mRNA increases after hydrocortisone infusion.109 In obese women and in normal-weight subjects, dexamethasone induces plasma leptin elevations that are unrelated to body fat distribution and insulin sensitivity.110 Indeed, metyrapone-induced inhibition of cortisol biosynthesis results in hypoleptinemia in obese subjects.111

Smoking

Nicotine increases plasma adrenaline levels. Plasma leptin levels in smoking men are lower than in nonsmokers. Nicotine may indirectly reduce leptin secretion via enhanced plasma catecholamine concentration.112 Murine recombinant leptin induces release of both epinephrine and norepinephrine from chromaffin cells. Moreover, leptin enhances nicotine-induced increases in catecholamines.113 Nicotine downregulates plasma leptin concentration and leptin mRNA. On the other hand, long-term nicotine administration increases expression of OB-Rb mRNA and OB-R mRNA in the medial basal hypothalamus compared with control rats.114 Indeed, leptin levels are higher in nicotine gum chewers and smokers than in the nonsmoking matched middle-aged men.115

Miscellaneous

All-trans retinoic acid reduces both expression and secretion of leptin in human and rodent adipose tissue.116 After 12 weeks of a high-glycemic index starch diet, both plasma leptin and ob mRNA are decreased compared with a low-glycemic index diet in rats.117 N-3 polyunsaturated fatty acids decrease leptin gene expression in human trophoblast cell lines.118 However, this treatment upregulates plasma leptin in insulin-sensitive rats.119 On a rapeseed oil diet, serum leptin concentrations increase slightly in men but decrease distinctly in women. Serum leptin levels may be affected by the large amount of α-linolenic acid in rapeseed oil. However, questions remain about why this diet differentially affects serum leptin in men and women.120

Future Prospects

In some contexts, leptin seems to promote both atherogenesis and and insulin resistance. By contrast, in other contexts, leptin may have antiatherogenic and insulin-sensitizing effects. These opposing actions of leptin are maintained in balance under healthy conditions. In pathological conditions such as obesity, the balance of leptin actions may shift to stimulate vascular inflammation, oxidative stress, and vascular smooth muscle hypertrophy. These actions may contribute to the pathogenesis of hypertension, atherosclerosis, left ventricular hypertrophy, and type 2 diabetes mellitus. Several clinical studies demonstrate that hyperleptinemia predicts acute cardiovascular events, restenosis after coronary injury, and cerebral stroke independent of traditional risk factors.12-14 By contrast, some data indicate that leptin may protect against atherosclerosis in specific animal models.15 Indeed, low plasma leptin predicts cardiovascular mortality.17

Leptin may potentiate the pressor effects of hyperinsulinemia in insulin-resistant states. Therefore, interactions between Ang II and insulin with leptin under insulin-resistant conditions may have deleterious cardiovascular effects in obesity. Positive and independent associations between leptin and insulin resistance suggest a role for leptin in the metabolic syndrome.87 However, human studies specifically examining the interactions between cardiovascular actions of insulin and leptin in normal and pathological states are lacking.

The antiatherogenic and insulin-sensitizing effects of leptin are summarized in Table 1. Therapeutic interventions with lifestyle modification, cardiovascular drugs, antidiabetic drugs, and miscellaneous therapies may be promising but still controversial (Table 2). Prospective studies are needed to examine the ability of decreases in leptin levels and increases in insulin sensitivity to improve primary end points including incidence of diabetes mellitus and outcomes of cardiovascular events. We summarize the stimulators and inhibitors of leptin expression in Table 3. It is possible that recombinant leptin may have a beneficial therapeutic role in the treatment and prevention of cardiovascular diseases in the future.

Table 1. Properties of Leptin Related to Cardiovascular Homeostasis.

References
Atherogenic properties of leptin
 Leptin and endothelial cells
  Upregulates inducible NO synthase; large amounts of NO may impair endothelial function through generation of peroxynitrite 23
  Impairs NO-dependent vasorelaxation induced by acetylcholine at pathophysiologically relevant “obese-range” concentrations 25
  Correlates with plasma level of soluble thrombomodulin and vascular cell adhesion molecule 27
  Stimulates synthesis and secretion of endothelin-1 by human umbilical vein endothelial cells 42
 Leptin and lipid profile
  Stimulates lipoprotein lipase secretion by cultured human and murine macrophages 31
  Enhances accumulation of cholesterol esters in foam cells at high glucose concentrations 32
  Promotes hepatic HDL clearance by upregulating scavenger receptor type B1 and decreases plasma HDL level 35
 Leptin and inflammatory markers
  Potentiates secretion of tumor necrosis factor and interleukins 2 and 6 in cells 36
  Generates reactive oxygen species and enhances expression of monocyte chemoattractant protein-1 37
  Produces proinflammatory cytokines from cultured monocytes and enhances production of Th1-type cytokines from stimulated lymphocytes 38
  Stimulates expression of CRP in human primary hepatocytes 20
  Stimulates transforming growth factor-β synthesis by endothelial cells 39
 Leptin and smooth muscle cells
  Stimulates migration and proliferation of vascular smooth muscle cells 40
  Stimulates expression of matrix metalloproteinase by vascular smooth muscle cells 40
  Induces expression of preproendothelin-1 and endothelin ETA receptor genes in rabbit smooth muscle cells 42
  Stimulates angiotensinogen and angiotensin type 1 receptor expression 41
  Stimulates osteoblastic differentiation and hydroxyapatite production by calcifying vascular cells 43
 Leptin and reactive oxidative stress
  Increases formation of reactive oxygen species in a process coupled with increased fatty acid oxidation and activation of protein kinase A 37
  Stimulates reactive oxygen species formation through endothelin and NADPH oxidase-dependent pathways 40,46
  Decreases paraoxonase 1 activity 45
 Leptin and thrombosis
  Increases expression of P-selectin on human platelets in vitro 48
  Promotes ADP-induced platelet aggregation 49
  Correlates with urinary excretion of 11-dehydrothromboxane B2, a marker of platelet activity 51
  Correlates with plasma concentration of plasminogen activator inhibitor-1, fibrinogen, and von Willebrand factor 52,53,54
  Inversely correlates with tissue plasminogen activator, protein kinase C, and tissue factor pathway inhibitors 54,55
 Leptin and Ang II
  Plasma renin activity, serum angiotensinogen, and leptin levels are correlated in humans 58,59
  Increases sympathetic nervous system activity 60
Antiatherogenic properties of leptin
 Elicits endothelium-dependent NO-mediated vasorelaxation in vitro and ex vivo 22
 Protects macrophages from cholesterol overload under normoglycemic conditions 33
 Corrects impaired antioxidant defense in ob/ob mice 44
Anti-insulin-resistant properties of leptin
 Increases insulin sensitivity in rats and may improve vascular responses to insulin in states of insulin resistance 64
 Insulin stimulates leptin secretion by adipocytes 65
 Increases glycogen synthesis in cultured C2C12 muscle cells 70
Insulin-resistant properties of leptin
 Negatively regulates insulin signaling 66
 Downregulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1 67
 Attenuates both antioxidative and lipogenic effects of insulin 68
 Inhibits glycogen synthesis in soleus muscle of ob/ob mice in the presence of insulin 69
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Table 2. Effects of Therapeutic Interventions on Leptin Levels.

References
Lifestyle modifications
 Diet control decreases plasma leptin levels 90
 Weight loss decreases leptin levels 27,91
 A diet rich in fish is associated with lower plasma leptin, independent of body fat 92
Recombinant human leptin
 Leptin treatment improves metabolic phenotype in patients with lipodystrophies or patients with leptin mutations 21,93
Renin-angiotensin system blocking agents
 Candesartan and captopril abolish the effect of Ang II to promote leptin production in human fat cells 56,57
 Ang II type 1 receptor blockers improve insulin resistance and reduce plasma leptin and leptin mRNA in rat adipose tissue 95
 Losartan treatment has no significant effect on leptin concentrations in patients with hypertension 96
 Perindopril does not decrease leptin in patients with hypertension 97
 Valsartan significantly reduces plasma leptin in patients with hypertension 98
 Ramipril combined with candesartan decreases leptin levels in patients with hypertension 30
 Ramipril and candesartan monotherapy significantly decreases plasma leptin levels in patients with hypertension 99
Calcium channel blockers
 Felodipine does not decrease leptin in patients with hypertension 97,98
 Amlodipine therapy significantly decreases plasma leptin levels in patients with hypertension 99
 Efonidipine treatment significantly decreases plasma leptin levels in patients with hypertension 28
β-Blockers
 Pindolol has a suppressive effect on leptin levels in hypertensive patients 97
 Atenolol therapy increases plasma leptin levels in hypertensive patients 99
Thiazide drugs
 Thiazide therapy does not change plasma leptin levels in hypertensive patients 99
Statins
 Atorvastatin reduces serum leptin concentration in hypercholesterolemic rabbits 100
 Pravastatin does not change leptin levels in healthy volunteers 101
 Lovastatin does not change leptin levels in nondiabetic patients 102
PPARα and PPARγ agonists
 Thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes 103
 Rosiglitazone and gemfibrozil decrease serum leptin levels in diet-induced obese rats 104
 PPARα activation decreases serum leptin levels in obese diabetic KKAy mice, but rosiglitazone does not 105
α1-Receptor blockers
 Bunazosin hydrochloride reduces plasma leptin levels in hypertensive patients with obesity and hyperleptinemia 106
Metformin
 Metformin reduces fasting insulin and leptin in morbidly obese, nondiabetic subjects 107
Dopamine D2 receptor agonist
 Bromocriptine lowers circulating leptin levels in obese women 108
Glucocorticoids
 Hydrocortisone induces hyperleptinemia in healthy adults 109
 Dexamethasone induces plasma leptin elevations in obese women and in normal-weight subjects 110
 Metyrapone-induced inhibition of cortisol biosynthesis results in hypoleptinemia in obese subjects 111
Smoking
 Cigarette smoking reduces plasma leptin concentration in men 112
 Long-term use of nicotine is associated with elevated circulating leptin levels in men 115
Miscellaneous
 All-trans retinoic acid reduces both expression and secretion of leptin in human and rodent adipose tissue 116
 High-glycemic index starch diet decreases both plasma leptin and ob mRNA in rats 117
 N-3 polyunsaturated fatty acids decreases leptin gene expression in a human trophoblast cell line 118
 N-3 polyunsaturated fatty acids upregulate plasma leptin in insulin-sensitive rats 119
 Rapeseed oil diet increases serum leptin concentrations in men but decreases leptin levels in women 120
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PPAR indicates peroxisome proliferator-activated receptor.

Table 3. Regulators of Leptin Expression.

References
Stimulators
 Stretching the vascular wall induces expression of both leptin and its receptor in the rabbit portal vein 41
 Ang II increases leptin synthesis in cultured adipose cells and in rats 56,57
 Insulin stimulates leptin secretion by adipocytes 65
 Hydrocortisone stimulates leptin mRNA expression in human adipocytes 109
 Chronic nicotine administration increases expression levels of OB-Rb mRNA and OB-R mRNA in rats 114
 N-3 polyunsaturated fatty acids upregulate plasma leptin in insulin-sensitive rats 119
Inhibitors
 Thiazolidinediones inhibit leptin (ob) gene expression in rats and 3T3-L1 adipocytes 103
 Nicotine downregulates plasma leptin concentration and leptin mRNA expression 114
 All-trans retinoic acid reduces both expression and secretion of leptin in human and rodent adipose tissue 116
 High-glycemic index starch diet decreases both plasma leptin and ob mRNA in rats 117
 N-3 polyunsaturated fatty acids decreases leptin gene expression in the human trophoblast cell line 118
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Acknowledgments

Sources of Funding

This study was supported in part by grants from Established Investigator Award (2007-1), Gil Medical Center, Gachon University (Dr Koh), and by the Intramural Research Program, National Center for Complementary and Alternative Medicine, National Institutes of Health (Dr Quon).

Footnotes

Disclosures

None.

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