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Does Genetic Variation in the Leptin Receptor Influence the Sympathetic Tone in Obesity?

The prevalence of obesity is increasing at an alarming rate throughout the world. Obesity is a serious health problem because weight gain is associated with a high risk of developing various diseases such as type 2 diabetes, some cancers and cardiovascular disorders including coronary heart disease, hypertension and endothelial dysfunction (1). The discovery of leptin in 1994 has allowed a tremendous advance in the endocrinology of energy homeostasis and the neurobiology of obesity. Leptin is an adipocyte-derived hormone whose circulating concentration is proportional to the level of body fat (2). This hormone is considered to be a critical signal that feeds back to inform the central nervous system about the status of peripheral energy reserves. The severe obesity and hyperphagia caused by the absence of leptin or its receptor in rodents and humans make it clear that this hormone is fundamental for the control of body weight and energy homeostasis (2–4). However, mutations in the genes that encode leptin or the leptin receptor are rare and most obese humans and rodents do not have low circulating leptin, but are hyperleptinemic, reflecting a state of leptin resistance just like hyperinsulinemia in type 2 diabetes is interpreted to reflect a state of insulin resistance. The understanding of the biological actions of leptin has increased exponentially during the recent years. Leptin is now recognized to have a broader range of actions with physiological implications that far surpass its influence on energy homeostasis. For instance, leptin is known to influence every aspect of reproduction including puberty onset, fertility and pregnancy (5, 6). Leptin also plays an important role in the neuroendocrine response to calorie restriction and starvation by modulating the hypothalamic pituitary function and the thyroid, adrenal and growth hormone axes (7–9). Leptin action in the central nervous system causes widespread activation of the sympathetic nervous system (10–12). The finding that leptin deficiency in humans is associated with decreased sympathetic tone and hypotension provides strong evidence for the importance of leptin for the control of the sympathetic nervous system (4). Emerging evidence supports a pathophysiological role for leptin in the hypertension associated with obesity because leptin resistance in the central nervous system appears selective. Indeed, the ability of leptin to activate the renal sympathetic nerve activity and increase arterial pressure is preserved in obesity despite the resistance to the metabolic actions of leptin (13). In the context of high circulating levels of leptin associated with obesity such selective leptin resistance could predispose to obesity-related hypertension and other cardiovascular diseases (14). In the current issue of Hypertension Research, Masuo et al. (15) examined whether genetic variation in the leptin receptor may contribute or determine the level of fat mass and sympathetic nerve activity in a Caucasian male population. The leptin receptor is a member of the cytokine family of receptors that have a single transmembrane domain. Alternative splicing of a single transcript encoded by the leptin receptor gene, mapped to 1p31, produces six different isoforms of the leptin