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      Serum IGF1 and linear growth in children with congenital leptin deficiency before and after leptin substitution

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          Abstract

          Background

          Evidence from in vitro and rodent studies suggests that leptin, a key signal of long-term energy reserves, promotes IGF1 synthesis and linear growth. This effect of leptin has not been fully investigated in humans. The aim of our study was to investigate the effect of leptin substitution on growth factors and linear growth in children with congenital leptin deficiency (CLD).

          Methods

          In this cohort study we included eight pediatric patients (six males), age 0.9–14.8 years, who were diagnosed with CLD and received leptin substitution at our University Medical Center. We calculated standard deviation scores (SDS) for serum levels of IGF1 and IGFBP3, IGF1/IGFBP3 molar ratio, and height at baseline (T0) and 12 months (T12) after the initiation of substitution with metreleptin.

          Results

          All patients had severe obesity (BMI-SDS mean ± SD: 4.14 ± 1.51) at T0 and significant BMI-SDS reduction to 2.47 ± 1.05 at T12. At T0, all patients were taller than the mid-parental median, yet had low IGF1 and IGF1/IGFBP3 molar ratios (IGF1-SDS \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\overline x$$\end{document} T0: −1.58 ± 0.92, IGF1/IGFBP3 molar ratio-SDS \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\overline x$$\end{document} T0: −1.58 ± 0.88). At T12, IGF1-SDS increased significantly (∆ T0–12: 1.63 ± 1.40, p = 0.01), and IGFBP3-SDS and IGF1/IGFBP3 molar ratio-SDS showed a trend toward an increase. In the three children within the childhood growth period (post-infancy, pre-puberty) height-SDS increased (∆height-SDS T0–12: 0.57 ± 0.06, p = 0.003) despite substantial weight loss.

          Conclusions

          These results in CLD patients are contrary to observations in children with idiopathic obesity who typically have above-mean IGF1 levels that decrease with weight loss, and therefore suggest that leptin increases IGF1 levels and promotes linear growth.

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          Most cited references57

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          Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben

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            Congenital leptin deficiency is associated with severe early-onset obesity in humans.

            The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.
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              Signalling by insulin and IGF receptors: supporting acts and new players.

              The signalling pathways utilised by insulin receptor (IR) and IGF receptor to transduce their diverse effects on cellular metabolism, growth and survival are well established in broad outline, but many details remain to be elucidated. Tyrosine phosphorylation of IR substrates and Shc initiates signalling via canonical phosphoinositide 3-kinase/Akt and Ras/MAP kinase pathways, which together mediate many of the actions of insulin and IGFs. However, a variety of additional substrates and scaffolds have been described that may play roles in modulating the canonical pathways or in specific biological responses. This review will focus on recent studies that have extended our understanding of insulin/IGF signalling pathways, and the elements that may contribute to specificity.
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                Author and article information

                Contributors
                martin.wabitsch@uniklinik-ulm.de
                Journal
                Int J Obes (Lond)
                Int J Obes (Lond)
                International Journal of Obesity (2005)
                Nature Publishing Group UK (London )
                0307-0565
                1476-5497
                17 May 2021
                17 May 2021
                2021
                : 45
                : 7
                : 1448-1456
                Affiliations
                [1 ]Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Centre Ulm, Ulm, Germany
                [2 ]GRID grid.10388.32, ISNI 0000 0001 2240 3300, Pediatric Endocrinology and Diabetology Division, Children’s Hospital, , University of Bonn, ; Bonn, Germany
                [3 ]GRID grid.2515.3, ISNI 0000 0004 0378 8438, Division of Pediatric Endocrinology, Department of Pediatrics, , Boston Children’s Hospital, ; Boston, MA USA
                [4 ]GRID grid.414231.1, ISNI 0000 0004 0575 3167, The Jesse and Sara Lea Shafer Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, ; Petach Tikva, Israel
                [5 ]GRID grid.12136.37, ISNI 0000 0004 1937 0546, Sackler Faculty of Medicine, , Tel Aviv University, ; Tel Aviv, Israel
                [6 ]GRID grid.144189.1, ISNI 0000 0004 1756 8209, Obesity and Lipodystrophy Center at the Endocrinology Unit, , University Hospital of Pisa, ; Pisa, Italy
                [7 ]GRID grid.8664.c, ISNI 0000 0001 2165 8627, Center of Child and Adolescent Medicine, , Justus-Liebig University, ; Giessen, Germany
                [8 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Present Address: Division of Endocrinology and Metabolism, Department of Medicine III, , Medical University of Vienna, ; Vienna, Austria
                Author information
                http://orcid.org/0000-0001-6161-4004
                http://orcid.org/0000-0001-5640-4491
                http://orcid.org/0000-0002-2729-9175
                Article
                809
                10.1038/s41366-021-00809-2
                8236407
                34002033
                c8aeba21-fe5c-4e59-8b2a-5121b8c4a0e5
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 October 2020
                : 19 February 2021
                : 22 March 2021
                Categories
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                Custom metadata
                © Springer Nature Limited 2021

                Nutrition & Dietetics
                obesity,endocrine system and metabolic diseases
                Nutrition & Dietetics
                obesity, endocrine system and metabolic diseases

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