Leptin mutation and mycobacterial infection lead non-synergistically to a similar metabolic syndrome

Abstract

Introduction The leptin signaling pathway plays an important role as a key regulator of glucose homeostasis, metabolism control and systemic inflammatory responses. However, the metabolic effects of leptin on infectious diseases, for example tuberculosis (TB), are still little known. Objectives In this study, we aim to investigate the role of leptin on metabolism in the absence and presence of mycobacterial infection in zebrafish larvae and mice. Methods Metabolites in entire zebrafish larvae and the blood of mice were studied using high-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy and mass spectrometry, respectively. For transcriptome studies of zebrafish larvae, deep RNA sequencing was used. Results The results show that leptin mutation leads to a similar metabolic syndrome as caused by mycobacterial infection in the two species, characterized by the decrease of 11 amine metabolites. In both species, this metabolic syndrome was not aggravated further when the leptin mutant was infected by mycobacteria. Therefore, we conclude that leptin and mycobacterial infection are both impacting metabolism non-synergistically. In addition, we studied the transcriptomes of lepbibl54 mutant zebrafish larvae and wild type (WT) siblings after mycobacterial infection. These studies showed that mycobacteria induced a very distinct transcriptome signature in the lepbibl54 mutant zebrafish compared to WT sibling control larvae. Furthermore, lepbibl55 Tg (pck1:luc1) zebrafish line was constructed and confirmed this difference in transcriptional responses. Conclusions Leptin mutation and TB lead non-synergistically to a similar metabolic syndrome. Moreover, different transcriptomic responses in the lepbibl54 mutant and TB can lead to the similar metabolic end states.

Transcriptomic and Metabolomic Studies Reveal That Toll-like Receptor 2 Has a Role in Glucose-Related Metabolism in Unchallenged Zebrafish Larvae (Danio rerio)

“…RNA sequencing of unchallenged tlr2 mutant and wild type zebrafish larvae were conducted by GenomeScan B.V. (Leiden, The Netherlands) as previously described [32]. Sequencing data of three biological replicates for the tlr2 mutant and wild type control were aligned and mapped to the zebrafish genome GRCz11 using Salmon v1.2.1 [33].…”

“…For the purpose of NMR spectroscopy, the method used to extract metabolites from zebrafish larvae in wild type and mutant groups was based on our previous research methods [32,39,40]. Briefly, each sample contained 120 zebrafish larvae at 5 dpf in a mixture of methanol: water (1:1, v/v) with 1 mL of chloroform.…”

“…NMR analysis was performed based on previous research [32,[40][41][42]. First, onedimensional (1-D) 1 H NMR spectra obtained from both in the wild type and mutant groups were corrected for baseline and phase shifts using MestReNova software version 11.0 (Mestrelab Research S.L., Santiago de Compostela, Spain).…”