José María Moreno-Navarrete1,2, Mariona Jove3, Francisco Ortega1,2, Gemma Xifra1,2, Wifredo Ricart1,2, Èlia Obis3, Reinald Pamplona3, Manuel Portero-Otin3, José Manuel Fernández-Real4,5. 1. 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. 2. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 3. Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida (IRBLleida)-PCiTAL, Lleida, Spain. 4. 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. 5. 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.
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.
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.
Authors: Evan D Rosen; Chung-Hsin Hsu; Xinzhong Wang; Shuichi Sakai; Mason W Freeman; Frank J Gonzalez; Bruce M Spiegelman Journal: Genes Dev Date: 2002-01-01 Impact factor: 11.361
Authors: Mariona Jové; José C E Serrano; Nàdia Ortega; Victòria Ayala; Neus Anglès; Jordi Reguant; José R Morelló; Maria Paz Romero; Maria José Motilva; Joan Prat; Reinald Pamplona; Manuel Portero-Otín Journal: J Proteome Res Date: 2011-06-17 Impact factor: 4.466
Authors: Francisco J Ortega; Josep M Mercader; José M Moreno-Navarrete; Lara Nonell; Eulàlia Puigdecanet; José I Rodriquez-Hermosa; Oscar Rovira; Gemma Xifra; Ester Guerra; María Moreno; Dolores Mayas; Natalia Moreno-Castellanos; José A Fernández-Formoso; Wifredo Ricart; Francisco J Tinahones; David Torrents; María M Malagón; José M Fernández-Real Journal: J Clin Endocrinol Metab Date: 2015-08-07 Impact factor: 5.958
Authors: Mariona Jové; José María Moreno-Navarrete; Reinald Pamplona; Wifredo Ricart; Manuel Portero-Otín; José Manuel Fernández-Real Journal: FASEB J Date: 2013-11-21 Impact factor: 5.191