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Leptin-Mediated Changes in the Human Metabolome.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Lawler, Katherine 
Huang-Doran, Isabel  ORCID logo  https://orcid.org/0000-0002-0573-6557
Sonoyama, Takuhiro 
Collet, Tinh-Hai 
Keogh, Julia M 

Abstract

CONTEXT: While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. OBJECTIVE: The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. DESIGN: Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. RESULTS: Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. CONCLUSION: Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin's effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.

Description

Keywords

bile acids, leptin, lipids, metabolomics, obesity, Adolescent, Child, Child, Preschool, Chromatography, Liquid, Energy Intake, Energy Metabolism, Female, Hormone Replacement Therapy, Humans, Leptin, Lipolysis, Loss of Function Mutation, Male, Metabolome, Metabolomics, Obesity, Recombinant Proteins, Severity of Illness Index, Tandem Mass Spectrometry, Treatment Outcome

Journal Title

J Clin Endocrinol Metab

Conference Name

Journal ISSN

0021-972X
1945-7197

Volume Title

105

Publisher

The Endocrine Society

Rights

All rights reserved
Sponsorship
Wellcome Trust (207462/Z/17/Z)
Wellcome Trust (208363/Z/17/Z)
MRC (MC_UU_00014/5)