Elsevier

Seminars in Nephrology

Volume 33, Issue 1, January 2013, Pages 54-65
Seminars in Nephrology

Overview of the Physiology and Pathophysiology of Leptin With Special Emphasis on its Role in the Kidney

https://doi.org/10.1016/j.semnephrol.2012.12.005Get rights and content

Summary

The adipocyte product leptin is a pleiotropic adipokine and hormone, with a role extending beyond appetite suppression and increased energy expenditure. This review summarizes the biology of the leptin system and the roles of its different receptors in a multitude of cellular functions in different organs, with special emphasis on the kidney. Leptin's physiological functions as well as deleterious effects in states of leptin deficiency or hyperleptinemia are emphasized. Chronic hyperleptinemia can increase blood pressure through the sympathetic nervous system and renal salt retention. The concept of selective leptin resistance in obesity is emerging, whereby leptin's effect on appetite and energy expenditure is blunted, with a concomitant increase in leptin's other effects as a result of the accompanying hyperleptinemia. The divergence in response likely is explained by different receptors and post-receptor activating mechanisms. Chronic kidney disease is a known cause of hyperleptinemia. There is an emerging view that the effect of hyperleptinemia on the kidney can contribute to the development and/or progression of chronic kidney disease in selective resistance states such as in obesity or type 2 diabetes mellitus. The mechanisms of renal injury are likely the result of exaggerated and undesirable hemodynamic influences as well as profibrotic effects.

Section snippets

Structure

The leptin (ob) gene is located on chromosome 6 in mice and on chromosome 7 in human beings; the 2 genes are 84% homologous and contain 3 exons.10 The gene product, leptin, is a 16-kDa protein made up of 167 amino acids.12 The amino terminal contains a secretory sequence made up of 21 amino acids, which is spliced upon leptin release into the circulation, so that serum leptin is actually made up of 146 amino acids.13 The leptin-receptor gene is located on chromosome 4 in mice and chromosome 1

Functional Effects of Leptin

Leptin is emerging as a pleiotropic hormone with a role extending beyond that of appetite suppression and increased energy expenditure.22 It acts as a signal of the body's nutritional status to the reproductive system, the immune system, the cardiovascular system, the skeletal system, and the thyroid hormone axis. Furthermore, it has a regulatory role on glycemia through effects on the liver and the pancreas, and on blood pressure both directly and through the sympathetic nervous system.

Chronic Kidney Disease Causes Hyperleptinemia

As a small peptide, leptin principally is cleared by the kidney, through a megalin-mediated tubular uptake, followed by endocytosis and intracellular degradation.15, 16, 55 Therefore, little or no leptin appears in urine. The megalin receptor is located in the proximal convoluted tubule and is responsible for the clearance of several hormones, such as prolactin, parathyroid hormone, and insulin.34 Consistently, leptin levels are increased in megalin knock-out mice models. In human beings,

Clinical Application and Future Directions

Leptin-receptor antagonists have been used previously for other disorders such as autoimmunity.82 Studies using leptin antagonists in renal disease specifically are lacking. In hyperleptinemia of obesity, administration of an antagonist in hypertensive rats, with either diet-induced obesity or with leptin overexpression, revealed an improvement in blood pressure only in the latter.83 Furthermore, leptin antagonism increased body weight as may be expected. Selective leptin antagonism would be

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