Review article
Effects of leptin on cardiovascular physiology

https://doi.org/10.1016/j.jash.2007.04.001Get rights and content

Abstract

Since the discovery of leptin, numerous studies have established a central role for this adipose tissue hormone in the regulation of body weight. Further it is now recognized that obesity is a state of hyperleptinemia resulting from increased synthesis and release of leptin from the greater adipose tissue mass present in this condition. Leptin has been implicated in the regulation of a number of physiological processes in addition to body weight homeostasis, and in many cases the hyperleptinemia of obesity may result in pathologic consequences. Leptin appears to have a central role in the development of obesity related hypertension and a number of observations implicate leptin as contributing to atherogenesis and atherosclerosis. Although significant progress has been made in our understanding of the pathologic effects of leptin on cardiovascular function, additional work remains to be done to fully understand the consequences of hyperleptinemia on cardiovascular physiology.

Introduction

The discovery of leptin synthesis and secretion from adipose tissue was a result of studies to understand the genetic basis for obesity in the ob/ob mouse.1 Shortly after the identification of leptin as a secretory product of adipose tissue a number of laboratories demonstrated that administration of the exogenous hormone resulted in inhibition of food intake and weight loss in mice.2 The leptin receptor was then identified as a hypothalamic protein, and a point mutation within the gene implicated as the defect resulting in obesity in db/db mice.3, 4 Taken together these observations, as well as numerous other related findings, established a central role for leptin in regulation of body weight. However, the demonstration of elevated leptin in obese humans and animals, and that the leptin receptor point mutation in the db/db mouse was not present in the human leptin receptor, suggested that most human obesity was not the result of single gene mutations identified in these mouse obesity models. Thus, in analogy to the concept of insulin resistance, it was suggested that obese humans were resistant to the weight-reducing effects of leptin.2, 5 Further, findings from a number of laboratories suggest that the hyperleptinemia resulting from the inability of leptin to reduce adipose tissue mass in obesity may have pathologic consequences, particularly on the cardiovascular system. In this article the cellular and neural mechanisms through which the leptin signal is propagated are reviewed with respect to the development of leptin resistance. Deleterious effects of hyperleptinemia on cardiovascular physiology are then evaluated in the context of whole body physiology and with attention to differences between physiologic and pharmacologic effects.

Section snippets

Leptin Receptors and Leptin Signaling

The leptin receptor is present in almost all tissues examined. The best-studied isoform, the hypothalamic leptin receptor Ob-Rb, is a class I cytokine receptor.6 Upon leptin binding, activation of Ob-Rb promotes janus kinase (JAK)-dependent signaling through signal transducer and activator of transcription (STAT) proteins, primarily STAT-3.7 This leptin receptor has also been observed to activate phosphoinositol-3 kinase and phosphodiesterase 3B signaling pathways in the hypothalamus,8, 9

Leptin Resistance

The concept of leptin resistance was originally proposed to explain the observation that elevated levels of the hormone did not reduce food intake or prevent body weight gain in obese humans.5, 18 Subsequently several molecular possibilities have been put forth to explain the mechanism of leptin resistance. Feeding a high fat diet decreases the effectiveness of peripherally injected leptin to induce weight loss in rodents.19, 20 As previously described, Ob-Ra is present on cerebral microvessels

Effects of Leptin on Cardiovascular Physiology

Elevated serum leptin has been associated with cardiovascular disease including stroke, chronic heart failure, acute myocardial infarction, coronary heart disease, and left cardiac hypertrophy.23, 24 Many of these studies suggest that the effect of leptin is independent of adiposity, although correction for measures of adiposity may not be sufficient if body fat distribution is not also taken into account. For example, a recent report adjusting for body fat distribution and insulin levels

Conclusions

The discovery of leptin 13 years ago1 began a new era of research that recognized adipose tissue as an active endocrine organ rather than just a passive reservoir for storage of fatty acids. An extensive amount of work since that time has established that leptin influences many physiological processes in addition to body weight homeostasis. However, hyperleptinemia resulting from resistance to the weight-reducing effects of leptin can result in pathology. In particular, the evidence is fairly

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    This study has been supported by National Institutes of Health Grants DK51140 (R.V.C.) and HL67804 (J.D.T.) and a grant from the American Diabetes Association (R.V.C.).

    Conflict of interest: none.

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