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Leptin: a pivotal regulator of human energy homeostasis

¹ From the University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.

² Presented at the symposium "Leptin: Weight Management and Beyond," held at Experimental Biology 2008, San Diego, CA, 6 April 2008.

³ Reprints not available. Address correspondence to IS Farooqi, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom. E-mail: isf20{at}cam.ac.uk

The identification of the hormone leptin by Friedman et al (1) in 1994 has proved to be a seminal observation in biomedical science. The discovery that a circulating protein secreted almost exclusively by adipocytes could regulate body weight through its effects on food intake and energy expenditure represented a remarkable breakthrough in our understanding of the molecular components of the systems involved in energy homeostasis. In this article, we describe how the identification of humans with mutations in the gene encoding leptin and the characterization of the associated clinical phenotype of congenital leptin deficiency, which includes hyperphagia, severe obesity, hypogonadism, and impaired immunity, has provided insights into the role of leptin-responsive pathways in the regulation of eating behavior, intermediary metabolism, and the onset of puberty. We and others have also been able to demonstrate that leptin signaling plays a critical role in the regulation of reproductive and immune function in humans, which places leptin at the center of the complex networks that coordinate changes in nutritional state with many diverse aspects of mammalian biology.

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