Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals

Yiran Zheng; Luisa Sophie Rajcsanyi; Manuela Kowalczyk; Johanna Giuranna; Beate Herpertz-Dahlmann; Jochen Seitz; Martina de Zwaan; Wolfgang Herzog; Stefan Ehrlich; Stephan Zipfel; Katrin Giel; Karin Egberts; Roland Burghardt; Manuel Föcker; Saad Al-Lahham; Johannes Hebebrand; Dagmar Fuhrer; Susanne Tan; Denise Zwanziger; Triinu Peters; Anke Hinney

doi:10.3389/fendo.2023.1137308

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals

Front Endocrinol (Lausanne). 2023 Mar 21:14:1137308. doi: 10.3389/fendo.2023.1137308. eCollection 2023.

Authors

Yiran Zheng^{1

2}, Luisa Sophie Rajcsanyi^{1

2}, Manuela Kowalczyk³, Johanna Giuranna¹, Beate Herpertz-Dahlmann⁴, Jochen Seitz⁴, Martina de Zwaan⁵, Wolfgang Herzog⁶, Stefan Ehrlich^{7

8}, Stephan Zipfel^{9

10}, Katrin Giel^{9

10}, Karin Egberts¹¹, Roland Burghardt¹², Manuel Föcker¹³, Saad Al-Lahham¹⁴, Johannes Hebebrand^{1

2}, Dagmar Fuhrer^{3

15}, Susanne Tan¹⁵, Denise Zwanziger³, Triinu Peters^{1

2}, Anke Hinney^{1

2}

Affiliations

¹ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
³ Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry - Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁴ Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany.
⁵ Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany.
⁶ Department of Internal Medicine II, General Internal and Psychosomatic Medicine, University of Heidelberg, Heidelberg, Germany.
⁷ Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, TU-Dresden, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
⁸ Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁹ Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital, Tübingen, Germany.
¹⁰ Centre of Excellence for Eating Disorders, University of Tübingen, Tübingen, Germany.
¹¹ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
¹² Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Oberberg Fachklinik Fasanenkiez, Berlin, Germany.
¹³ Department of Child and Adolescent Psychiatry, University of Münster, Münster, Germany.
¹⁴ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine.
¹⁵ Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Abstract

Context: The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway.

Objective: We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level.

Methods: Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes.

Results: Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033).

Conclusion: Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

Keywords: Energy homeostasis; GWAS; bone marrow; lean body mass (LBM); secondary structure of protein.

Copyright © 2023 Zheng, Rajcsanyi, Kowalczyk, Giuranna, Herpertz-Dahlmann, Seitz, de Zwaan, Herzog, Ehrlich, Zipfel, Giel, Egberts, Burghardt, Föcker, Al-Lahham, Hebebrand, Fuhrer, Tan, Zwanziger, Peters and Hinney.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Anorexia Nervosa* / genetics
Child
Female
Humans
Lipocalin-2* / genetics
Mutation
Obesity / metabolism
Obesity, Morbid*

Substances

Lipocalin-2
LCN2 protein, human

Grants and funding

This study was funded by the Deutsche Forschungsgemeinschaft (DFG; HI 865/2-1), the BMBF (01GS0820; PALGER 2017-33: 01DH19010) and the Stiftung Universitätsmedizin Essen.