BioMed Central Page 1 of 4 (page number not for citation purposes) Thyroid Research Open Access Short report Congenital leptin deficiency and thyroid function Gilberto Paz-Filho 1 , Tuncay Delibasi 2 , Halil K Erol 3 , Ma-Li Wong 1 and Julio Licinio* 1 Address: 1 The John Curtin School of Medical Research, The Australian National University, Canberra ACT, Australia, 2 Ankara Numune Research and Training Hospital, Endocrinology and Metabolism Clinic, Ankara, Turkey and 3 Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA Email: Gilberto Paz-Filho - g.paz@uol.com.br; Tuncay Delibasi - tuncay@delibasi.net; Halil K Erol - hkerol@yahoo.com; Ma- Li Wong - maliwong@me.com; Julio Licinio* - jlicinio@mac.com * Corresponding author Abstract : Thyroid function is closely related to leptin's secretion by the adipose tissue. In states of leptin- deficiency, the circadian rhythm of TSH is altered, leading to central hypothyroidism in animal models. In humans, central hypothyroidism has also been described in rare cases of congenital leptin deficiency. However, the thyroid phenotype in these cases is heterogeneous, with the occurrence of central hypothyroidism in a minority of cases. Here we describe thyroid function in four leptin-deficient humans (2 males aged 5 and 27, and 2 females aged 35 and 40), before and during leptin replacement with recombinant human methionyl leptin (r-metHuLeptin). The child was evaluated for four years, and the adults, for eight years. In addition, the adults were submitted to a brief withdrawal of leptin during six weeks in the sixth year. Our results show that, regardless of leptin replacement, our leptin-deficient patients have normal thyroid function. In spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function. Trial Registration: ClinicalTrials.gov Identifiers: NCT00659828 and NCT00657605 Findings There is evidence that the hypothalamic-pituitary-thyroi- dal axis is regulated, at least in part, by leptin. This pro- vides an important interface between adiposity, regulated by leptin, and metabolic rate, regulated by thyroid hor- mones. The mechanisms underlying the connection between adipose signals and energy expenditure include the regulation of the synthesis and secretion of TRH (thy- rotropin releasing hormone) by leptin, through the medi- ation of input from the arcuate nucleus to the TRH neurons in the paraventricular nucleus (PVN) [1]. In addi- tion, the thyroid axis is also indirectly regulated by leptin's actions on the melanocortin pathway, as alpha-MSH (melanocyte stimulating hormone) stimulates and AgRP (agouti-related protein) blocks TRH release [2]. Further- more, leptin has direct effects on TRH neurons, regulating its synthesis not only by up-regulating the expression of the proTRH gene in the PVN [3] and by influencing the feedback regulation of the TRH-secreting neurons by thy- roid hormones, but also by increasing promoter activities of the prohormone convertases PC1/3 and PC2, essential for the activation of TRH from proTRH [4]. In leptin-deficient humans, different thyroid phenotypes have been reported. In three children of Pakistani origin, thyroid function tests were within the normal range Published: 4 November 2009 Thyroid Research 2009, 2:11 doi:10.1186/1756-6614-2-11 Received: 17 July 2009 Accepted: 4 November 2009 This article is available from: http://www.thyroidresearchjournal.com/content/2/1/11 © 2009 Paz-Filho et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.