Lessons from the leptin paradox in cardiac regulation--too much versus too little.

Propelled by identification of the obese gene product leptin and its metabolic property in food intake and energy expenditure, renewed interest has been generated in characterizing the cardiovascular pathology associated with obesity. As a multifactorial disease involving both genetic and lifestyle factors, uncorrected obesity often leads to cardiac hypertrophy, ventricular dysfunction, reduced diastolic compliance and a cluster of metabolic syndromes including diabetes, hypertension, insulin resistance and hyperlipidaemia (Eckel et al. 2002). Although several mechanisms have been postulated for obesity-associated cardiac dysfunctions such as gene mutation, salt sensitivity, insulin resistance, sympathetic activation and lifestyle factors, none of these factors has been considered the ultimate culprit of cardiac abnormalities in obesity. To add to the complexity, metabolic syndromes such as diabetes and hypertension are often concurrent with obesity and obscure the independent impact of obesity on heart function. Recent evidence revealed that obesity is commonly associated with increased plasma leptin levels and/or interrupted leptin signalling due to either abnormal expression of leptin and/or the leptin receptor. Plasma leptin levels (5–15 ng ml−1 in lean subjects) are significantly elevated in all forms of rodent (with exception of the ob/ob mice due to a nonsense mutation of the leptin gene) and human obesity, whether of genetic, hypothalamic or dietary origin (Ren, 2004), suggesting the state of hyperleptinaemic ‘leptin resistance’ in obesity. With the potent pleiotropic actions of leptin, it is postulated, though paradoxically, that hyperleptinaemia is involved in the pathogenesis of obesity. Obesity is believed to be the major stimulator of leptin production with hyperphagia and caloric restriction being responsible for enhanced or decreased leptin levels, respectively (Wang et al. 2001). Other than its central regulation of food intake and energy expenditure, leptin exerts a wide variety of bodily functions in reproductive, renal and cardiovascular systems. Given the high propensity of heart diseases in obesity and the profound expression of the leptin receptor in cardiomyocytes, the regulatory effect of leptin on cardiac function and remodelling has drawn ever increasing attention recently (Barouch et al. 2003; Ren, 2004). Leptin has been demonstrated to regulate both myocardial contractility (Ren, 2004) and cellular growth (Barouch et al. 2003). Ventricular myocytes from hyperleptinaemic rats exhibit impaired post-receptor leptin signalling and contractile function (Ren, 2004). Mice lacking leptin (ob/ob) or its receptor (db/db) develop cardiac hypertrophy independent of body weight, strongly supporting a role for intact leptin signalling in maintaining normal cardiac architecture (Barouch et al. 2003). However, it is still difficult to reconcile the fact that leptin deficiency actually leads to ventricular hypertrophy in the laboratory setting (ob/ob mice) despite the fact that clinical cardiac hypertrophy is commonly found in hyperleptinaemia. In this issue of The Journal of Physiology, Hare and colleagues reported impaired cardiac β-adrenergic response in cardiomyocytes from the leptin-deficient ob/ob mice, which was restored with recombinant leptin infusion (Minhas et al. 2005). They observed depressed sarcomere shortening, Ca2+ transients and sarcoplasmic reticulum (SR) Ca2+ load in cardiomyocytes from ob/ob mice following stimulation at the β-receptor (with isoproterenol (isoprenaline)) or at the post-receptor (with forskolin and dibutryl-cAMP) levels, which were consistent with the high-fat diet-induced obesity with elevated plasma leptin levels (J. Ren, D. P. Relling and E. C. Carlson, unpublished data). Depressed or desensitized cardiac β-adrenergic responsiveness is also a hallmark for heart failure and cardiac complications in diabetes and obesity. Perhaps the most intriguing data from Hare's study was that leptin replenishment restored all functional abnormalities and reduced protein kinase A activity in ob/ob mice without affecting gross (wall thickness) or microscopic (cell size) measures of cardiac architecture, indicating potential regulatory benefit of leptin on cardiac function independent of structural morphology. In addition, leptin repletion reconciled altered expression of proteins in β-adrenergic response (reduced Gsα) and intracellular Ca2+ cycling (increased SERCA and depressed phosphorylated phospholamban). These data provided a novel link between the leptin signalling pathway and cardiac function and suggested a mechanism by which leptin deficiency may lead to cardiac dysfunction. It is worth mentioning that a fall in leptin not only impairs cardiac function but also leads to immune deficiency (e.g. lymphoid atrophy and T-lymphocyte dysfunction), which may be restored by leptin replenishment. This depressed immune defence may itself contribute to compromised cardiac function. One other interesting note from Hare's study was that the enhanced plasma insulin and triglyceride levels in ob/ob mice were reconciled by leptin replenishment, indicating a close relationship among leptin, insulin and fatty acid signalling. An increase in plasma leptin levels may reduce insulin release and enhance insulin sensitivity. However, long-term hyperleptinaemia will eventually down-regulate insulin signalling and induce insulin resistance through over-phosphorylation of insulin receptor substrate (IRS)-1/IRS-2 and depletion of phosphatidylinositol-3 kinase (Ren, 2004). The role of leptin in lipid metabolism is of interest and may participate in cardiac regulation of the hormone. Leptin is capable of oxidizing excessive long-chain fatty acids to benefit cardiac function. Such leptin-induced fatty acid oxidation may become abnormal under leptin deficiency or resistance, allowing unoxidized fatty acids to enter non-oxidative pathways en route to cellular injury. Although leptin carries a label of an anti-obesity hormone, hyperleptinaemia and leptin resistance found in human obesity have surely ruined the reputation of the metabolic hormone – just like insulin resistance to insulin. Interrupted leptin signalling was reported in hyperleptinaemic conditions including cardiac contractile response to leptin (Ren, 2004), making hyperleptinaemia essentially comparable to leptin deficiency regarding leptin signalling. What may be different between the two conditions is the presence of ‘selective leptin resistance’ under hyperleptinaemia where the sympathoexcitatory action of leptin is preserved despite hormonal resistance to satiety and energy metabolism (Mark et al. 2002). This is attributed to poor penetration of leptin across the blood–brain barrier, making the hyperleptinaemic signal unable to trigger adequate feedback inhibition of the leptin production. The ‘selective leptin resistance’ dilemma illustrates why hyperleptinaemia in obesity links to increased sympathetic activity and arterial pressure in the presence of metabolic resistance to leptin. Leptin plays a physiological role but leptin resistance may be pathophysiological for metabolic and cardiovascular dysfunction under obesity. Understanding of the signalling mechanisms behind leptin deficiency and leptin resistance should have significant clinical value in managing obesity-associated heart diseases.