title: Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity.
abstract: OBJECTIVE
  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
  Overall, these results support the notion that in situ production of PLP is required for physiological adipogenesis.
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona 'Dr Josep Trueta', Carretera de França s/n, 17007, Girona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.affiliation: Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida (IRBLleida)-PCiTAL, Lleida, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Jove
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona 'Dr Josep Trueta', Carretera de França s/n, 17007, Girona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona 'Dr Josep Trueta', Carretera de França s/n, 17007, Girona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Xifra
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona 'Dr Josep Trueta', Carretera de França s/n, 17007, Girona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
authors.affiliation: Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida (IRBLleida)-PCiTAL, Lleida, Spain.
authors.forename: Èlia
authors.initials: È
authors.lastname: Obis
authors.affiliation: Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida (IRBLleida)-PCiTAL, Lleida, Spain.
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.affiliation: Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida (IRBLleida)-PCiTAL, Lleida, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona 'Dr Josep Trueta', Carretera de França s/n, 17007, Girona, Spain. jmfreal@idibgi.org.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, . jmfreal@idibgi.org.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernández-Real
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism; D011731:Pyridoxal Kinase / Q000378:metabolism*; D050151:Subcutaneous Fat / Q000378:metabolism; D025101:Vitamin B 6 / Q000378:metabolism
chemical_list: D025101:Vitamin B 6; D011731:Pyridoxal Kinase
keywords: Adipogenesis; Insulin sensitivity; Obesity; PDXK; Vitamin B6
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