J. Clin. Invest. 110:1093-1103 (2002). doi:10.1172/JCI200215693.
Copyright ©2002 by the American Society for Clinical Investigation
--------------------------------------------------------------------------------
Article
Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency
I. Sadaf Farooqi1, Giuseppe Matarese2, Graham M. Lord3, Julia M. Keogh1, Elizabeth Lawrence4, Chizo Agwu5, Veronica Sanna2, Susan A. Jebb6, Francesco Perna7, Silvia Fontana2, Robert I. Lechler3, Alex M. DePaoli4 and Stephen O’Rahilly1
1 University Department of Medicine and Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom 2 Centro di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR-CEOS), Naples, Italy 3 Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom 4 AMGEN Inc., Thousand Oaks, California, USA 5 Department of Paediatrics, Sandwell Hospital, West Midlands, United Kingdom 6 Medical Research Council, Human Nutrition Research, Cambridge, United Kingdom 7 Cattedra di Malattie dell’Apparato Respiratorio, Dipartimento di Medicina Clinica e Sperimantale, Universita di Napoli Frederico II, Naples, Italy
Address correspondence to: I. Sadaf Farooqi, University Department of Medicine and Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. Phone: 44 1223 762634; Fax: 44 1223 762657; E-mail: ifarooqi@hgmp.mrc.ac.uk.
Received for publication April 15, 2002, and accepted in revised form August 13, 2002.
The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents. In contrast, information regarding the roles of this hormone in humans is limited. Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia. Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development. Leptin deficiency was associated with reduced numbers of circulating CD4+ T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency. |
