Leptin Signaling and Obesity

Abstract

Abstract-Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated kinase/signal transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism, hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease. Extensive evidence now supports the notion that maladaptation of the biological system for weight maintenance makes it extremely difficult for people to maintain weight loss. 1 Several genes have been identified to disclose a physiological system that maintains body weight within a range of about twenty pounds. 2 A key element of this system is leptin, the 16-kDa hormonal product of the obesity (ob) gene. 3 Leptin is primarily secreted by adipocytes and is a classic member of the more than 50 identified adipocytokines that participate in adipose tissue hormonal signaling. 4 Since its identification in 1994, leptin has attracted much attention as one of the most important central and peripheral signals for the maintenance of energy homeostasis. [5][6][7][8] For example, a 9-year-old girl with extreme obesity was found to lack leptin. 9 Leptin treatment reduced her weight to the normal range for her age, and the same effects were observed in her similarly affected cousin. 10 Plasma leptin is generally proportional to adipose mass. 11,12 The primary physiological role of leptin is to communicate to the central nervous system (CNS) the abundance of available energy stores and to restrain food intake and induce energy expenditure. The absence of leptin therefore leads to increased appetite and food intake that result in morbid obesity. Notably, only rare cases of severe early childhood obesity have been associated with leptin deficiency. 9,13 The remainder of the obese population typically have elevated leptin levels. 14 The failure of leptin to induce weight loss in these cases is thought to be the result of leptin resistance.Hyperleptinemia, nearly universally observed in human obesity and animal models, is accompanied by a disruption of the usual activities of the hormone, possibly at different Original received May 22, 2007; revision received July 20, 2007; accepted August 6, 2007 18 -20 Obesity is also a part of the metabolic syndrome, which is diagnosed by a set of criteria that include abdominal obesity, insulin resistance, dyslipidemia, and hypertension. This patient population faces increased risk for type 2 diabetes and cardiovascular diseases. The widely distributed Ob-Rs make the hormone an attractive candidate for a molecul...

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