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4. Classification of Congenital Leptin Deficiency.

Author

Schnurbein, Julia von, Zorn, Stefanie, Nunziata, Adriana, Brandt, Stephanie, Moepps, Barbara, Funcke, Jan-Bernd, Hussain, Khalid, Farooqi, I Sadaf, Fischer-Posovszky, Pamela, and Wabitsch, Martin

Subjects
HORMONE deficiencies, BODY mass index, NOSOLOGY, LEPTIN, GENETIC variation
Abstract

Purpose Biallelic pathogenic leptin gene variants cause severe early-onset obesity usually associated with low or undetectable circulating leptin levels. Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties. Methods We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular and functional characteristics of the underlying leptin variants and investigated the correlation of disease subtype with severity of the clinical phenotype. Results A total of 28 distinct homozygous leptin variants were identified in 148 patients. The identified variants can be divided into 3 different subtypes of congenital leptin deficiency: classical hormone deficiency (21 variants in 128 patients), biologically inactive hormone (3 variants in 12 patients), and antagonistic hormone (3 variants in 7 patients). Only 1 variant (n = 1 patient) remained unclassified. Patients with biological inactive leptin have a higher percentage of 95th body mass index percentile compared to patients with classical hormone deficiency. While patients with both classical hormone deficiency and biological inactive hormone can be treated with the same starting dose of metreleptin, patients with antagonistic hormone need a variant-tailored treatment approach to overcome the antagonistic properties of the variant leptin. Main Conclusion Categorization of leptin variants based on molecular and functional characteristics helps to determine the most adequate approach to treatment of patients with congenital leptin deficiency. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Classification of Congenital Leptin Deficiency

Author

von Schnurbein, Julia, primary, Zorn, Stefanie, additional, Nunziata, Adriana, additional, Brandt, Stephanie, additional, Moepps, Barbara, additional, Funcke, Jan-Bernd, additional, Hussain, Khalid, additional, Farooqi, I Sadaf, additional, Fischer-Posovszky, Pamela, additional, and Wabitsch, Martin, additional

Published
2024
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8. Adipocyte iron levels impinge on a fat-gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity

Author

Zhang, Zhuzhen, Funcke, Jan-Bernd, Zi, Zhenzhen, Zhao, Shangang, Straub, Leon G., Zhu, Yi, Zhu, Qingzhang, Crewe, Clair, An, Yu A., Chen, Shiuhwei, Li, Na, Wang, May-yun, Ghaben, Alexandra L., Lee, Charlotte, Gautron, Laurent, Engelking, Luke J., Raj, Prithvi, Deng, Yingfeng, Gordillo, Ruth, Kusminski, Christine M., and Scherer, Philipp E.

Published
2021
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9. miR-146a regulates insulin sensitivity via NPR3

Author

Roos, Julian, Dahlhaus, Meike, Funcke, Jan-Bernd, Kustermann, Monika, Strauss, Gudrun, Halbgebauer, Daniel, Boldrin, Elena, Holzmann, Karlheinz, Möller, Peter, Trojanowski, Bernadette M., Baumann, Bernd, Debatin, Klaus-Michael, Wabitsch, Martin, and Fischer-Posovszky, Pamela

Published
2021
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11. Hyperleptinemia contributes to antipsychotic drug–associated obesity and metabolic disorders

Author

Zhao, Shangang, primary, Lin, Qian, additional, Xiong, Wei, additional, Li, Li, additional, Straub, Leon, additional, Zhang, Dinghong, additional, Zapata, Rizaldy, additional, Zhu, Qingzhang, additional, Sun, Xue-Nan, additional, Zhang, Zhuzhen, additional, Funcke, Jan-Bernd, additional, Li, Chao, additional, Chen, Shiuhwei, additional, Zhu, Yi, additional, Jiang, Nisi, additional, Li, Guannan, additional, Xu, Ziying, additional, Wyler, Steven C., additional, Wang, May-Yun, additional, Bai, Juli, additional, Han, Xianlin, additional, Kusminski, Christine M., additional, Zhang, Ningyan, additional, An, Zhiqiang, additional, Elmquist, Joel K., additional, Osborn, Olivia, additional, Liu, Chen, additional, and Scherer, Philipp E., additional

Published
2023
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12. Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity

Author

Funcke, Jan-Bernd, primary, Moepps, Barbara, additional, Roos, Julian, additional, von Schnurbein, Julia, additional, Verstraete, Kenneth, additional, Fröhlich-Reiterer, Elke, additional, Kohlsdorf, Katja, additional, Nunziata, Adriana, additional, Brandt, Stephanie, additional, Tsirigotaki, Alexandra, additional, Dansercoer, Ann, additional, Suppan, Elisabeth, additional, Haris, Basma, additional, Debatin, Klaus-Michael, additional, Savvides, Savvas N., additional, Farooqi, I. Sadaf, additional, Hussain, Khalid, additional, Gierschik, Peter, additional, Fischer-Posovszky, Pamela, additional, and Wabitsch, Martin, additional

Published
2023
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15. Frühkindlicher BMI-Verlauf bei monogener Adipositas

Author

Kohlsdorf, Katja, Nunziata, Adriana, Funcke, Jan-Bernd, Brandt, Stephanie, von Schnurbein, Julia, Vollbach, Heike, Lennerz, Belinda, Fritsch, Maria, Greber-Platzer, Susanne, Fröhlich-Reiterer, Elke, Borck, Guntram, Fischer-Posovszky, Pamela, and Wabitsch, Martin

Published
2017
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17. Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-independent Glucose Uptake via Extracellular Vesicles

Author

Crewe, Clair, primary, Chen, Shiuhwei, primary, Bu, Dawei, primary, Gliniak, Christy M., primary, Asterholm, Ingrid Wernstedt, primary, Yu, Xin Xin, primary, Joffin, Nolwenn, primary, Souza, Camila Oliveira de, primary, Funcke, Jan-Bernd, primary, Oh, Da Young, primary, Varlamov, Oleg, primary, Robino, Jacob J, primary, Gordillo, Ruth, primary, and Scherer, Philipp E., primary

Published
2022
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18. Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

Author

Zhu, Yi, primary, Li, Na, additional, Huang, Mingyang, additional, Chen, Xi, additional, An, Yu A., additional, Li, Jianping, additional, Zhao, Shangang, additional, Funcke, Jan-Bernd, additional, Cao, Jianhong, additional, He, Zhenyan, additional, Zhu, Qingzhang, additional, Zhang, Zhuzhen, additional, Wang, Zhao V., additional, Xu, Lin, additional, Williams, Kevin W., additional, Li, Chien, additional, Grove, Kevin, additional, and Scherer, Philipp E., additional

Published
2022
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21. Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-Independent Glucose Uptake via Extracellular Vesicles.

Author

Crewe, Clair, Chen, Shiuhwei, Bu, Dawei, Gliniak, Christy M., Wernstedt Asterholm, Ingrid, Yu, Xin Xin, Joffin, Nolwenn, de Souza, Camila O., Funcke, Jan-Bernd, Oh, Da Young, Varlamov, Oleg, Robino, Jacob J., Gordillo, Ruth, Scherer, Philipp E., and Oliveira de Souza, Camila

Abstract

Caveolin-1 (cav1) is an important structural and signaling component of plasma membrane invaginations called caveolae and is abundant in adipocytes. As previously reported, adipocyte-specific ablation of the cav1 gene (ad-cav1 knockout [KO] mouse) does not result in elimination of the protein, as cav1 protein traffics to adipocytes from neighboring endothelial cells. However, this mouse is a functional KO because adipocyte caveolar structures are depleted. Compared with controls, ad-cav1KO mice on a high-fat diet (HFD) display improved whole-body glucose clearance despite complete loss of glucose-stimulated insulin secretion, blunted insulin-stimulated AKT activation in metabolic tissues, and partial lipodystrophy. The cause is increased insulin-independent glucose uptake by white adipose tissue (AT) and reduced hepatic gluconeogenesis. Furthermore, HFD-fed ad-cav1KO mice display significant AT inflammation, fibrosis, mitochondrial dysfunction, and dysregulated lipid metabolism. The glucose clearance phenotype of the ad-cav1KO mice is at least partially mediated by AT small extracellular vesicles (AT-sEVs). Injection of control mice with AT-sEVs from ad-cav1KO mice phenocopies ad-cav1KO characteristics. Interestingly, AT-sEVs from ad-cav1KO mice propagate the phenotype of the AT to the liver. These data indicate that ad-cav1 is essential for healthy adaptation of the AT to overnutrition and prevents aberrant propagation of negative phenotypes to other organs by EVs. [ABSTRACT FROM AUTHOR]

Published
2022
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25. The mitochondrial dicarboxylate carrier prevents hepatic lipotoxicity by inhibiting white adipocyte lipolysis

Author

An, Yu A., primary, Chen, Shiuhwei, additional, Deng, Yingfeng, additional, Wang, Zhao V., additional, Funcke, Jan-Bernd, additional, Shah, Manasi, additional, Shan, Bo, additional, Gordillo, Ruth, additional, Yoshino, Jun, additional, Klein, Samuel, additional, Kusminski, Christine M., additional, and Scherer, Philipp E., additional

Published
2021
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26. miR-146a regulates insulin sensitivity via NPR3

Author

Roos, Julian, Dahlhaus, Meike, Funcke, Jan-Bernd, Kustermann, Monika, Strauss, Gudrun, Halbgebauer, Daniel, Boldrin, Elena, Holzmann, Karlheinz, Möller, Peter, Trojanowski, Bernadette M., Baumann, Bernd, Debatin, Klaus-Michael, Wabitsch, Martin, and Fischer-Posovszky, Pamela

Subjects
MicroRNAs, Adipocytes, Insulin resistance, ddc:610, NPR3, DDC 610 / Medicine & health, miRNS, Insulinresistenz, Fettzelle
Abstract

The pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a−/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a−/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3., publishedVersion

Published
2020

27. miR-146a regulates insulin sensitivity via NPR3

Author

Roos, Julian, primary, Dahlhaus, Meike, additional, Funcke, Jan-Bernd, additional, Kustermann, Monika, additional, Strauss, Gudrun, additional, Halbgebauer, Daniel, additional, Boldrin, Elena, additional, Holzmann, Karlheinz, additional, Möller, Peter, additional, Trojanowski, Bernadette M., additional, Baumann, Bernd, additional, Debatin, Klaus-Michael, additional, Wabitsch, Martin, additional, and Fischer-Posovszky, Pamela, additional

Published
2020
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28. CD90 Is Dispensable for White and Beige/Brown Adipocyte Differentiation

Author

Dahlhaus, Meike, primary, Roos, Julian, additional, Engel, Daniel, additional, Tews, Daniel, additional, Halbgebauer, Daniel, additional, Funcke, Jan-Bernd, additional, Kiener, Sophie, additional, Schuler, Patrick J., additional, Döscher, Johannes, additional, Hoffmann, Thomas K., additional, Zinngrebe, Julia, additional, Rojewski, Markus, additional, Schrezenmeier, Hubert, additional, Debatin, Klaus-Michael, additional, Wabitsch, Martin, additional, and Fischer-Posovszky, Pamela, additional

Published
2020
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29. Age- and BMI-Associated Expression of Angiogenic Factors in White Adipose Tissue of Children

Author

Gaebler, Niklas, primary, Haggenmüller, Benedikt, additional, Kapapa, Melanie, additional, Serra, Alexandre, additional, Tews, Daniel, additional, Funcke, Jan-Bernd, additional, Brandt, Stephanie, additional, Ioannidis, Valentin, additional, Schön, Michael, additional, Möller, Peter, additional, Debatin, Klaus-Michael, additional, Wabitsch, Martin, additional, and Fischer-Posovszky, Pamela, additional

Published
2019
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32. Estimated prevalence of potentially damaging variants in the leptin gene

Author

Nunziata, Adriana, primary, Borck, Guntram, additional, Funcke, Jan-Bernd, additional, Kohlsdorf, Katja, additional, Brandt, Stephanie, additional, Hinney, Anke, additional, Moepps, Barbara, additional, Gierschik, Peter, additional, Debatin, Klaus-Michael, additional, Fischer-Posovszky, Pamela, additional, and Wabitsch, Martin, additional

Published
2017
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34. Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency

Author

Wabitsch, Martin, primary, Pridzun, Lutz, additional, Ranke, Michael, additional, von Schnurbein, Julia, additional, Moss, Anja, additional, Brandt, Stephanie, additional, Kohlsdorf, Katja, additional, Moepps, Barbara, additional, Schaab, Michael, additional, Funcke, Jan-Bernd, additional, Gierschik, Peter, additional, Fischer-Posovszky, Pamela, additional, Flehmig, Bertram, additional, and Kratzsch, Jürgen, additional

Published
2017
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36. Functional and Phenotypic Characteristics of Human Leptin Receptor Mutations.

Author

Nunziata, Adriana, Funcke, Jan-Bernd, Borck, Guntram, Schnurbein, Julia von, Brandt, Stephanie, Lennerz, Belinda, Moepps, Barbara, Gierschik, Peter, Fischer-Posovszky, Pamela, and Wabitsch, Martin

Subjects
LEPTIN receptors, FUNCTIONAL analysis, PHENOTYPES
Abstract

Several case series of extreme early-onset obesity due to mutations in the human leptin receptor (LEPR) gene have been reported. In this review we summarize published functional and phenotypic data on mutations in the human LEPR gene causing severe early-onset obesity. Additionally, we included data on six new cases from our obesity center. Literature research was performed using PubMed and OMIM. Functional relevance of mutations was estimated based on reported functional analysis, mutation size, and location, as well as phenotypic characteristics of affected patients. We identified 57 cases with 38 distinct LEPR mutations. We found severe early-onset obesity, hyperphagia, and hypogonadotropic hypogonadism as cardinal features of a complete loss of LEPR function. Other features, for example, metabolic disorders and recurring infections, were variable in manifestation. Obesity degree or other manifestations did not aggregate by genotype. Few patients underwent bariatric surgery with variable success. Most mutations occurred in the fibronectin III and cytokine receptor homology II domains, whereas none was found in cytoplasmic domain. In silico data were available for 25 mutations and in vitro data were available for four mutations, revealing residual activity in one case. By assessing provided information on the clinical phenotype, functional analysis, and character of the 38 mutations, we assume residual LEPR activity for five additional mutations. Functional in vitro analysis is necessary to confirm this assumption. [ABSTRACT FROM AUTHOR]

Published
2019
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41. Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex.

Author

Li C, Sun XN, Funcke JB, Vanharanta L, Joffin N, Li Y, Prasanna X, Paredes M, Joung C, Gordillo R, Vörös C, Kulig W, Straub L, Chen S, Velasco J, Cobb A, Padula D, Wang MY, Onodera T, Varlamov O, Li Y, Liu C, Nawrocki AR, Zhao S, Oh DY, Wang ZV, Goodman JM, Wynn RM, Vattulainen I, Han Y, Ikonen E, and Scherer PE

Abstract

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98Å overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.

Published
2024
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