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STATE-OF-THE-ART PAPER

Leptin Resistance

A Possible Interface of Inflammation and Metabolism in Obesity-Related Cardiovascular Disease

Cardiovascular Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Manuscript received May 12, 2008; accepted May 28, 2008.

^_* Reprint requests and correspondence: Dr. Muredach P. Reilly, Cardiovascular Division, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160 (Email: muredach{at}spirit.gcrc.upenn.edu).

Leptin is an adipocyte-derived hormone and cytokine that regulates energy balance through a wide range of functions, including several that are important to cardiovascular health. Increased circulating leptin, a marker of leptin resistance, is common in obesity and independently associated with insulin resistance and cardiovascular disease (CVD) in humans. The mechanisms of leptin resistance include genetic mutation, leptin self-regulation, limited tissue access, and cellular or circulating molecular regulation. Evidence suggests that central leptin resistance causes obesity and that obesity-induced leptin resistance injures numerous peripheral tissues, including liver, pancreas, platelets, vasculature, and myocardium. This metabolic- and inflammatory-mediated injury may result from either resistance to leptin's action in selective tissues, or excess leptin action from adiposity-associated hyperleptinemia. In this sense, the term "leptin resistance" encompasses a complex pathophysiological phenomenon. The leptin axis has functional interactions with elements of metabolism, such as insulin, and inflammation, including mediators of innate immunity, such as interleukin-6. Leptin is even purported to physically interact with C-reactive protein, resulting in leptin resistance, which is particularly intriguing, given C-reactive protein's well-studied relationship to cardiovascular disease. Given that plasma levels of leptin and inflammatory markers are correlated and also predict cardiovascular risk, it is conceivable that part of this risk may be mediated through leptin resistance-related insulin resistance, chronic inflammation, type II diabetes, hypertension, atherothrombosis, and myocardial injury. Leptin resistance and its interactions with metabolic and inflammatory factors, therefore, represent potential novel diagnostic and therapeutic targets in obesity-related cardiovascular disease.

Key Words: obesity • leptin resistance • inflammation • atherosclerosis • cardiovascular disease

Abbreviations and Acronyms   BMI = body mass index   CVD = cardiovascular disease   CRP = C-reactive protein   IL = interleukin   JAK/STAT = janus kinase signal transduction and translation   MI = myocardial infarction   SLIP = serum leptin-interacting protein   SOCS3 = suppressor-of cytokine-signaling-3

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