Review Article
Leptin as a Cardiac Hypertrophic Factor: A Potential Target for Therapeutics

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The satiety factor leptin has received extensive attention especially in terms of its potential role in appetite suppression and regulation of energy expenditure. Once considered to be solely derived from adipose tissue, which accounts for the greatly increased levels observed in obese subjects, it is now apparent that leptin can be produced by a multiplicity of tissues, including the heart, where it appears to function in an autocrine and paracrine manner. Plasma leptin concentrations are also elevated in patients with heart disease including those with congestive heart failure. Leptin exerts its biological effects via a family of receptors termed Ob-R. In cardiac cells, one of leptin's primary actions is to produce cardiomyocyte hypertrophy through multifaceted cell signaling mechanisms including stimulation of mitogen-activated protein kinase and activation of the RhoA/Rho kinase (ROCK) pathway. The hypertrophic effect of leptin suggests that it may contribute to myocardial remodeling after cardiac injury and offers the potential targeting of the leptin system as a novel cardiac therapy.

Introduction

The discovery and cloning of the obesity gene (ob) in 1994 (Zhang et al. 1994) has led to an explosion of studies aimed at unraveling the molecular and cellular basis of obesity and its accompanying disorders. Although originally thought to represent a disease reflecting an imbalance between food intake and energy expenditure, the identification of ob and the demonstration of its overexpression in obesity lent credence to the notion of a biochemical and molecular basis for obesity. The finding that ob encodes a circulating satiety peptide, subsequently named leptin for the Greek word leptos, meaning thin, was particularly exciting in view of the peptide's potential for treating obesity.

Leptin, a 16-kDa pleiotropic peptide, exerts its effects via membrane-bound receptors, generally termed Ob-R (leptin receptors have also been referred to as LEPR, although the Ob-R terminology will be used here for consistency), which include various short forms possessing short intracellular domains (Ob-Ra, Ob-Rc, Ob-Rd, Ob-Rf) and a long form (Ob-Rb), which is highly homologous to the type I cytokine receptor family. Their structures are illustrated in Figure 1. Ob-Rb has a long intracellular domain and its activation is classically coupled to the activation of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) pathway.

Section snippets

Leptin as a Possible Link Between Obesity and Increased Cardiovascular Risk

The relationship between obesity and increased risk for the development of cardiovascular disease is well known (Okerberg and Hamilton, 2003, Sowers, 2003, Sundell, 2005), and obesity produces distinct changes in myocardial biochemistry, structure and function (Ricci et al., 2006, Wong and Marwick, 2007). Although a clear mechanistic basis for increased cardiovascular risk in obese individuals is uncertain, leptin has received some attention as a potential causative, or at least a contributing

Expression of Cardiac Leptin Receptors

The first demonstration of the presence of Ob-R gene expression in cardiac tissue was reported in 1996 upon the discovery of the gene encoding the db/db mutation (Lee et al. 1996). Further characterization of Ob-R isoforms indicated that cardiac tissue expressed Ob-Ra, Ob-Rb, and Ob-Re (Lollmann et al., 1997, Wold et al., 2002). Recent work from the authors' laboratory suggest that Ob-R gene expression in the heart differs in terms of regional distribution and is affected by gender (Purdham et

Effect of Leptin on Cardiomyocyte Function

Under in vivo conditions, the cardiovascular actions of leptin can be predicted based on the central sympathetic stimulatory effect of the peptide resulting in sympathetic nervous system–dependent effects such as elevations in blood pressure and positive inotropic and chronotropic effects. However, leptin can exert direct effects on both the heart and blood vessels through Ob-R–dependent cell signaling mechanisms. In isolated ventricular myocytes leptin produces a negative inotropic effect via

Plasma Leptin Levels are Elevated in Cardiac Disease States

Although the primary stimulus for elevation in plasma leptin concentrations is obesity and the concomitant increased adiposity, heart disease, in the absence of obesity is also associated with hyperleptinemia, although to a markedly lowered degree than that seen in the obese state. Increases in plasma leptin concentrations have been observed both in patients with ischemic heart disease (Wallace et al. 2001) and in patients with heart failure (Schulze et al. 2003), with evidence that

Leptin as a Cardiac Hypertrophic Factor

Evidence for leptin as a hypertrophic and progrowth factor stems primarily from studies examining the direct effect of the peptide on myocyte preparations and from in vivo studies (see Table 1) as well as a number of clinical studies that have demonstrated a significant relationship between plasma leptin levels and the degree of left ventricular hypertrophy under various pathologic conditions (Iacobellis et al., 2003, Paolisso et al., 1999). More importantly, such analyses do not prove a cause

Can Leptin Produce an Antihypertrophic Effect?

Despite the increasing evidence for a prohypertrophic effect of leptin, it is possible, in view of the diverse effect of the peptide, that leptin can produce other effects under certain conditions. A particular example is when leptin-deficient ob/ob mice have also been used to assess the possible contribution of the peptide to cardiac hypertrophy, with results opposite to those obtained with other approaches described above. Thus, Barouch et al. (2003) reported that leptin administration to

Post–Receptor Leptin Signaling Mediating Cardiomyocyte Hypertrophy

In general, the complexity and diversity of leptin's effects is exemplified by its ability to activate several signal transduction pathways. The discussion below focuses on signaling pathways that have been elucidated in cardiovascular tissue or that appear to be particularly relevant to understanding of leptin-mediated cardiac signaling and its possible relationship to cardiac hypertrophy as a potential target for cardiac therapeutics.

As previously alluded to, Ob-Rb is the fully competent

Summary and Conclusions

Since the first identification of leptin as a key satiety regulator there has been a tremendous explosion of research into this intriguing peptide, which is now known to exert a myriad of effects on a large number of tissues. The identification of leptin receptors in different tissues coupled with findings that diverse organs and tissues can produce leptin leads to the conclusion that leptin exerts effects that are substantially more extensive than initially thought. This clearly applies to the

Acknowledgments

The work described from the authors' laboratory is supported by the Canadian Institutes of Health Research. M. Karmazyn holds a Canada Research Chair in Experimental Cardiology. D. M. Purdham holds a Scholarship from the Heart and Stroke Foundation of Canada. A. Zeidan is supported by the Heart and Stroke Foundation of Ontario Program in Heart Failure.

References (40)

  • A. Aneja et al.

    Hypertension and obesity

    Recent Prog Horm Res

    (2004)
  • L.A. Barouch et al.

    Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice

    Circulation

    (2003)
  • F. Charron et al.

    Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA

    Genes Dev

    (2001)
  • G. Grassi

    Leptin, sympathetic nervous system, and baroreflex function

    Curr Hypertens Rep

    (2004)
  • J.E. Hall et al.

    Impact of the obesity epidemic on hypertension and renal disease

    Curr Hypertens Rep

    (2003)
  • K.K. Hintz et al.

    Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes

    Int J Obes Relat Metab Disord

    (2003)
  • G. Iacobellis et al.

    Relationship of insulin sensitivity and left ventricular mass in uncomplicated obesity

    Obes Res

    (2003)
  • G.H. Lee et al.

    Abnormal splicing of the leptin receptor in diabetic mice

    Nature

    (1996)
  • G. Loirand et al.

    Rho kinases in cardiovascular physiology and pathophysiology

    Circ Res

    (2006)
  • M.W. Nickola et al.

    Leptin attenuates cardiac contraction in rat ventricular myocytes. Role of NO

    Hypertension

    (2000)
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