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Congenital leptin deficiency and thyroid function
Thyroid Research volume 2, Article number: 11 (2009)
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.
ClinicalTrials.gov Identifiers: NCT00659828 and NCT00657605
There is evidence that the hypothalamic-pituitary-thyroidal axis is regulated, at least in part, by leptin. This provides an important interface between adiposity, regulated by leptin, and metabolic rate, regulated by thyroid hormones. The mechanisms underlying the connection between adipose signals and energy expenditure include the regulation of the synthesis and secretion of TRH (thyrotropin releasing hormone) by leptin, through the mediation of input from the arcuate nucleus to the TRH neurons in the paraventricular nucleus (PVN) . In addition, 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 . Furthermore, leptin has direct effects on TRH neurons, regulating its synthesis not only by up-regulating the expression of the proTRH gene in the PVN  and by influencing the feedback regulation of the TRH-secreting neurons by thyroid hormones, but also by increasing promoter activities of the prohormone convertases PC1/3 and PC2, essential for the activation of TRH from proTRH .
In leptin-deficient humans, different thyroid phenotypes have been reported. In three children of Pakistani origin, thyroid function tests were within the normal range before the start of recombinant human methionyl leptin (r-metHuLeptin) therapy, with a rise in free T4 (fT4) thereafter in all children, and an increase in T3 in the two youngest . In another child, also of Pakistani origin, subclinical hypothyroidism was diagnosed before treatment, with high TSH and normal T4 levels . Treatment with levothyroxine (LT4) was initiated before r-metHuLeptin, with a decrease in TSH levels. After the initiation of r-metHuLeptin, fT4 levels increased above the upper limit of the reference range, leading to the interruption of LT4 therapy. While on r-metHuLeptin, off LT4, thyroid function and TSH response to TRH were normal, which gives further support to the hypothesis that the hypothalamic-pituitary-thyroidal is regulated by leptin.
We would like to document here that the phenotype of leptin-deficient patients is highly heterogeneous, by reporting the findings on thyroid function in leptin-deficient patients of Turkish origin. We have been studying three adults (1 male and 2 females) and one boy from a highly consanguineous Turkish family. Those patients have a nonconservative missense leptin gene mutation (cysteine-to-threonine in codon 105), which renders them leptin-deficient. We previously described the effects of treatment with r-metHuLeptin, started at ages 5 (male patient A) , 27 (male patient B), 35 and 40 (female patients C and D, respectively) .
As opposed to the findings in one child of Pakistani origin, our leptin-deficient boy (A) had normal thyroid function before, two and four years after the initiation of r-metHuLeptin. In addition, we have not observed an increase in fT4 or T3 levels after the initiation of r-metHuLeptin (Table 1).
Similarly, the leptin-deficient adults also have normal thyroid function, both before and after the initiation of r-metHuLeptin. Six years after the initiation of treatment, a brief withdrawal of leptin during six weeks was undertaken. No significant changes in thyroid hormones were observed (Table 1). In spite of having normal thyroid function, we have previously shown that the absence of leptin disorganizes the circadian rhythm of TSH . In addition, levels of anti-thyroid antibodies were normal in our patients, at all times.
Based on our data we conclude that in spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function. Why does leptin deficiency cause different thyroid phenotypes? Leptin is truly pleiotropic, with multiple effects that can directly or indirectly affect thyroid function. Therefore, thyroid dysfunction, in a leptin-deficient state, may exist due to diverse combinations of factors that may vary across patients. In addition, age may be an important determinant of thyroid dysfunction, as only the youngest child showed laboratorial alterations related to thyroid function. It is important to note that not only the thyroid phenotype is heterogeneous among leptin-deficient patients. In comparison with the patients of Pakistani origin, our patients had higher body mass index (BMI), but lower insulin levels and insulin resistance index (HOMA-IR), as illustrated in Table 2. This heterogeneity was observed even among the Turkish patients for several parameters. In addition, the therapeutic regimen was slightly different in both groups of patients, regarding the time of administration of leptin (in the morning vs. in the evening for our patients - mimicking leptin's circadian rhythm). Nevertheless, in both protocols, dose was adjusted based on clinical response. That heterogeneous phenotype may be explained by several factors, such as a different concentration of leptin soluble receptor, leading to variations in free leptin levels. So far, the molecular mechanisms by which different mutations in the leptin gene lead to the presence or absence of thyroid dysfunction is unknown.
The multidirectional action of leptin in thyroid axis should also be taken into account. Thyroid hormones can stimulate the transcription of leptin gene through adrenergic effects. Although endogenous hyperthyroidism can lead to higher leptin levels, short-term treatment does not change leptinemia , neither does the induction of hyperthyroid states in healthy males . Another study showed that hypothyroid patients have lower leptinemia . In our study, since all patients were euthyroid, this multidirectional action does not apply.
In conclusion, we show here that thyroid dysfunction is not a constant in leptin deficiency. The identification of factors that lead to hypothyroidism in some, but not all, leptin-deficient patients will provide better understanding of the roles of leptin on the hypothalamic-pituitary-thyroidal axis. New insight on the interaction between leptin and thyroid function will be gained from future studies aimed at identifying the factors that protect our leptin-deficient patients from clinical thyroid dysfunction, even in the presence of an abnormal circadian rhythm of TSH.
body mass index
high-density lipoprotein cholesterol
homeostasis model of assessment of insulin resistance
low-density lipoprotein cholesterol
melanocyte stimulating hormone
recombinant human methionyl leptin
thyrotropin releasing hormone.
Legradi G, Emerson CH, Ahima RS, Rand WM, Flier JS, Lechan RM: Arcuate nucleus ablation prevents fasting-induced suppression of ProTRH mRNA in the hypothalamic paraventricular nucleus. Neuroendocrinology 1998, 68: 89–97. 10.1159/000054354
Kim MS, Small CJ, Stanley SA, Morgan DG, Seal LJ, Kong WM, Edwards CM, Abusnana S, Sunter D, Ghatei MA, Bloom SR: The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. J Clin Invest 2000, 105: 1005–1011. 10.1172/JCI8857
Nillni EA, Vaslet C, Harris M, Hollenberg A, Bjorbak C, Flier JS: Leptin regulates prothyrotropin-releasing hormone biosynthesis. Evidence for direct and indirect pathways. J Biol Chem 2000, 275: 36124–36133. 10.1074/jbc.M003549200
Nillni EA: Regulation of prohormone convertases in hypothalamic neurons: implications for prothyrotropin-releasing hormone and proopiomelanocortin. Endocrinology 2007, 148: 4191–4200. 10.1210/en.2007-0173
Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O'Rahilly S: Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002, 110: 1093–1103.
Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O'Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 2004, 89: 4821–4826. 10.1210/jc.2004-0376
Paz-Filho GJ, Babikian T, Asarnow R, Delibasi T, Esposito K, Erol HK, Wong ML, Licinio J: Leptin replacement improves cognitive development. PLoS ONE 2008, 3: e3098. 10.1371/journal.pone.0003098
Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004, 101: 4531–4536. 10.1073/pnas.0308767101
Mantzoros CS, Ozata M, Negrao AB, Ziotopoulou M, Caglayan S, Suchard M, Cogswell RJ, Negro P, Elashoff RM, Liberty V, Wong M-L, Veldhuis JD, Ozdemir IC, Gold PW, Flier JS, Licinio J: Synchronicity of frequently sampled TSH and leptin concentrations in healthy adults and leptin deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab 2001, 86: 3284–3291. 10.1210/jc.86.7.3284
Ozata M, Ozisik G, Bingol N, Corakci A, Gundogan MA: The effects of thyroid status on plasma leptin levels in women. J Endocrinol Invest 1998, 21: 337–341.
Mantzoros CS, Rosen HN, Greenspan SL, Flier JS, Moses AC: Short-term hyperthyroidism has no effect on leptin levels in man. J Clin Endocrinol Metab 1997, 82: 497–499. 10.1210/jc.82.2.497
Yoshida T, Momotani N, Hayashi M, Monkawa T, Ito K, Saruta T: Serum leptin concentrations in patients with thyroid disorders. Clin Endocrinol (Oxf) 1998, 48: 299–302. 10.1046/j.1365-2265.1998.00408.x
We thank the patients for their willingness to participate in the study.
The authors declare that they have no competing interests.
All authors contributed equally to conception and design, acquisition of data, analysis and interpretation of data; manuscript drafting and final approval was also done by all authors.
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Paz-Filho, G., Delibasi, T., Erol, H.K. et al. Congenital leptin deficiency and thyroid function. Thyroid Res 2, 11 (2009). https://doi.org/10.1186/1756-6614-2-11
- Thyroid Function
- Thyroid Dysfunction
- Central Hypothyroidism
- Normal Thyroid Function
- Pakistani Origin