COMMENTARIES

Obesity-Hypertension: Emerging Concepts of Neuroendocrine Dysregulation

Garry P. Reams, M.D.¹, Daniel Villarreal, M.D., FACC, FAHA, FIACS²,³, and Robert M. Spear, M.S.³, ¹Department of Internal Medicine, University of Missouri-Columbia, Columbia, MO, ²Professor of Medicine, Chief, Division of Cardiology, ³SUNY Upstate Medical University and Veterans Affairs Medical Center, 750 East Adams Street, Syracuse, NY ¹³²¹0

Introduction

The prevalence of obesity in the adult population of the United States has risen markedly in the past three decades and is presently greater than 30% [1]. This epidemic of obesity represents a serious health hazard with significant morbidity and mortality [1,2]. Indeed, obesity is associated with multiple metabolic alterations, which in turn promote widespread atherogenesis [1,3]. This cluster of disturbances, collectively known as the metabolic syndrome, includes dyslipidemia, insulin resistance, glucose intolerance, and hypertension, and may also be associated with proinflammatory and prothrombotic states [3]. Although it has become increasingly apparent that individuals with the metabolic syndrome are at enhanced risk for cardiovascular and renal disease, the precise etiology of this disorder, and the underlying mechanisms that link its various components remain incompletely defined. Recently, it has been suggested that insulin resistance, which plays a major role in the pathophysiology of metabolic syndrome may in part be secondary to leptin resistance, which in turn is highly prevalent in obesity [4]. Moreover, in the past 5 to 10 years increasing information indicates that leptin can uniquely and directly influence autonomic, cardiovascular, and renal functions in physiologic and pathophysiologic situations. Consequently, leptin may be an important link in the pathogenesis of the hypertension and heart disease induced by obesity and the metabolic syndrome [5].

 

Chronic Hyperleptinemia, Leptin Resistance, and Hypertension

It is well established that leptin can activate the sympathetic nervous system and promote vasoconstriction both by peripheral actions and centrally mediated effects on the hypothalamus [6,7]. However, other investigations have also determined that leptin promotes vasorelaxation primarily through endothelial stimulation of nitric oxide, (NO) [8,9]. Thus, under normal conditions, leptin is thought to have a neutral effect on arterial blood pressure, and this response may represent a balanced action of vasodilation mediated by NO, and vasoconstriction mediated by the sympathetic nervous system [9].

          However, in chronic hyperleptinemic conditions such as obesity, the potential neutral effect of leptin on the peripheral vascular resistance may not remain. Relevant to this concept, it is pertinent to point out that obesity is characterized by abnormal NO production and metabolism [10]. The resultant NO deficiency, in turn, could lead to the preponderance of leptin-induced vasoconstriction via the continuous and unopposed stimulation of sympathetic nervous system. To this end, previous studies have indicated that the agouti yellow mouse model of obesity is resistant to the hypothalamic actions of leptin for appetite suppression, but not to the effects of leptin for the enhancement of the sympathetic nervous system [11]. From the latter findings, the concept of “selective leptin resistance” as a mechanism for the development of hypertension in obesity has emerged [11]. Accordingly, it has been suggested that in some obese patients with hyperleptinemia, there is resistance to the satiety action of leptin but the sympathetic overactivity leading to elevated blood pressure is preserved.

              Independent of the possibility of selective leptin resistance in obesity, studies in lean animal models of chronic hyperleptinemia have demonstrated a persistent mean arterial pressure elevation of 15 to 20 mm Hg, which is promptly reversed upon cessation of leptin administration, [12]. Moreover, a similar hypertensive effect has been found in transgenic mice overexpressing leptin [13]. Although, the relevance of this basic research information in the context of human hypertension remains to be established, increasing evidence indicates a significant positive correlation between circulating levels of leptin and blood pressure in adolescents and adults, even independent of body weight [14,15]. Furthermore, it has been reported that elevated plasma levels of leptin exist in healthy offspring of hypertensive patients; and this possible genetic predisposition could contribute to the development of hypertension [16]. Thus, this emerging collective knowledge suggests that chronic hyperleptinemia and leptin resistance may function pathophysiologically to elevate arterial blood pressure via its autonomic, vascular, and renal effects [16].

 

Leptin and the Kidney

Several in vitro investigations have indicated that the renal medulla, and particularly the inner medullary collecting duct, contains the long-tail leptin receptor (LRb) [17], which in turn suggests a functional role of this hormone in renal biology. Indeed, numerous studies have demonstrated that acute administration of synthetic leptin in the rat produces a significant elevation in urinary sodium and water excretion [5,32], but these actions are absent in hypertensive and obese rat models. These findings have been interpreted to suggest that leptin might be a natriuretic hormone primarily acting at the tubular level to promote sodium excretion in normal rats, but it may function pathophysiologically in obesity and hypertension, where chronic hyperleptinemia may contribute to a preferential stimulation of the sympathetic nervous system with further elevation in blood pressure and reduced sodium excretion [2,18]. Moreover, studies in rat models of diet-induced obesity have shown markedly attenuated natriuretic and diuretic effects of synthetic leptin and markedly reduced urinary excretion of NO [2,5]. These findings suggest that in obesity, alterations in leptin-induced renal NO production and/or metabolism may account, at least in part, for the blunted natriuretic effects. However, additional observations in the diet-induced obese rats indicate that long-term caloric restriction was associated with restoration of the natriuretic actions of leptin and with the renal generation of NO [5]. In the aggregate, these studies are consistent with the concept that obesity is associated with renal leptin resistance, and this resistance, at least in part, is reversible with weight loss [5,19].

          Thus, leptin’s net effect on renal sodium metabolism may reflect both direct natriuretic and indirect antinatriuretic actions. The responsiveness to leptin at the renal, neural, and possibly other sites may differ under various physiologic and pathophysiologic conditions, and this, in turn, will determine the overall magnitude of leptin-induced urinary sodium excretion.

 

Leptin and the Heart 

It is now well recognized that the role of leptin in energy homeostasis extends to cardiac metabolism. The effects of leptin include inhibition of insulin signaling with enhanced lipid oxidation, and therefore inhibiting anabolic pathways and reducing energy storage. These actions are mediated via the LRb receptor, which has been demonstrated to exist in the heart [17].

              Similar to the kidney, chronic hyperleptinemia may be important indirectly in the development of cardiac disease via sympathetic activation, pressor effects, enhancement of platelet aggregation, impairment of fibrinolysis, and proangiogenic actions [6,12,20,21]. In addition, and although still controversial, leptin may be involved in the pathogenesis of myocyte hypertrophy and cardiac dysfunction through direct effects. Indeed, leptin can proliferate, differentiate, and functionally activate hemopoietic and embryonic cells to promote myocyte growth [22]. Among the suggested mechanisms involved are the stimulation of angiotensin II, endothelin-1, and reactive oxygen species levels [23]. Finally, it has been reported that this hypertrophic effect on ventricular myocytes, as evidenced by increased cell surface area, protein synthesis, and expression of the fetal gene, α-skeletal actin and MLC-2, a constitutive gene, can occur with physiologically relevant concentrations of leptin [24].

              In addition to its potential actions on myocardial cell growth, leptin has been shown to exert a direct negative inotropic effect on adult rat ventricular myocytes [25]. The suggested mechanisms involve activation of fatty acid oxidation leading to decreased triglyceride content, or an altered adenylate cyclase function [26]. Alternatively, Nickola et al. [25] reported that leptin may abnormally increase expression of NO synthases in cardiac myocytes, promoting oxidative stress and ultimately depressed cardiac function.

              From the clinical perspective, the available evidence suggests a direct relationship between the hyperleptinemia of obesity with cardiac hypertrophy [27,28] and possibly heart failure [10,29]. In this regard, the potential deleterious direct effects of leptin on cardiac myocytes may be worsened by the possible role of this hormone in the development of atherogenesis. The suggested mechanisms include the promotion of oxidative stress and oxidized low-density lipoprotein, and the generation of prothrombotic and proinflammatory cytokines [30]. However, whether hyperleptinemia—independent of obesity or the metabolic syndrome—is associated with increased cardiovascular events remains controversial. It is clear that additional basic and clinical research are needed to better define and characterize the potential links between leptin and cardiac disease. 

 

Conclusions and Perspectives

It is well established that cardiovascular and renal functions require the activation of multiple neurohormonal mechanisms designed to maintain stability. Leptin, the recently discovered antiobesity hormone, has multiple actions that may be important not only for energy metabolism, but also in cardiovascular and renal regulation. Potentially prominent are its effects on renal sodium excretion, sympathetic nervous system activation, and vascular tone. The interaction among the vasoconstricting, vasodilatory, and natriuretic effects of leptin that help to achieve volume and pressure homeostasis in normal conditions may be disrupted during chronic hyperleptinemia, an effect likely to contribute to hypertension. Further research awaits the characterization of additional direct and indirect mechanisms of action of leptin, including its interface with other important hormonal sodium-volume-pressure regulatory systems in both health and disease, particularly in obesity and related comorbidities. This information could lead to the development of leptin analogues and LR receptor blockers that, under specific circumstances, could optimize the beneficial actions of the hormone and minimize its deleterious effects.

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