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Diabetologia
Published in: Diabetologia 4/2016

01-04-2016 | Article

Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity

Authors: José María Moreno-Navarrete, Mariona Jove, Francisco Ortega, Gemma Xifra, Wifredo Ricart, Èlia Obis, Reinald Pamplona, Manuel Portero-Otin, José Manuel Fernández-Real

Published in: Diabetologia | Issue 4/2016

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Abstract

Aims/hypothesis

We aimed to investigate the potential mechanisms involved in the compromised adipogenesis of visceral (VAT) vs subcutaneous adipose tissue (SAT) using comparative metabolomics. Based on the differentially identified metabolites, we focused on the relationship between the active form of vitamin B6 (pyridoxal 5-phosphate [PLP]), known to be generated through pyridoxal kinase (PDXK), and adipogenesis.

Methods

Non-targeted metabolomics analyses were performed in paired VAT and SAT (n = 14, discovery cohort). PDXK gene expression was evaluated in two validation cohorts of paired SAT and VAT samples in relation to obesity status and insulin sensitivity, and mechanistically after weight loss in vivo and in 3T3-L1 cells in vitro.

Results

Comparative metabolomics showed that PLP was significantly decreased in VAT vs SAT. Concordantly, PDXK mRNA levels were significantly decreased in VAT vs SAT, specifically in adipocytes. The decrease was specially marked in obese individuals. PDXK mRNA levels showed a strong association with adipogenic, lipid-droplet-related and lipogenic genes. At a functional level, systemic insulin sensitivity positively associated with PDXK expression, and surgically-induced weight loss (improving insulin sensitivity) led to increased SAT PDXK mRNA levels in parallel with adipogenic genes. In human pre-adipocytes, PDXK mRNA levels increased during adipocyte differentiation and after administration of peroxisome proliferator-activated receptor-γ agonists, and decreased under inflammatory stimuli. Mechanistic studies in 3T3-L1 cells showed that PLP administration resulted in increased adipogenic mRNA markers during early adipogenesis, whereas the PLP antagonist 4-deoxypyridoxine exerted opposite effects.

Conclusions/interpretation

Overall, these results support the notion that in situ production of PLP is required for physiological adipogenesis.
Appendix
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Metadata
Title
Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity
Authors
José María Moreno-Navarrete
Mariona Jove
Francisco Ortega
Gemma Xifra
Wifredo Ricart
Èlia Obis
Reinald Pamplona
Manuel Portero-Otin
José Manuel Fernández-Real
Publication date
01-04-2016
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 4/2016
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-3863-1

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