title: Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis.
abstract: Obesity is linked to adipose tissue hypertrophy (increased adipocyte cell size) and hyperplasia (increased cell number). Comparative analyses of gene datasets allowed us to identify 1426 genes which may represent common adipose phenotype in humans and mice. Among them we identified several adipocyte-specific genes dysregulated in obese adipose tissue, involved in either fatty acid storage (acyl CoA synthase ACSL1, hormone-sensitive lipase LIPE, aquaporin 7 AQP7, perilipin PLIN) or cell adhesion (fibronectin FN1, collagens COL1A1, COL1A3, metalloprotein MMP9, or both (scavenger receptor FAT/CD36). Using real-time analysis of cell surface occupancy on xCELLigence system we developed a new method to study lipid uptake and differentiation of mouse 3T3L1 fibroblasts and human adipose stem cells. Both processes are regulated by insulin and fatty acids such as oleic acid. We showed that fatty acid addition to culture media increased the differentiation rate and was required for full differentiation into unilocular adipocytes. Significant activation of lipogenesis, i.e. lipid accumulation, by either insulin or oleic acid was monitored in times ranging from 1 to 24 h, depending on differentiation state, whereas significant effects on adipogenesis, i.e., surperimposed lipid accumulation and gene transcriptional regulations were measured after 3 to 4 d. Combination of selected times for analysis of lipid contents, cell counts, size fractionations, and gene transcriptional regulations showed that FAT/CD36 specific inhibitor AP5258 significantly increased cell survival of oleic acid-treated mouse and human adipocytes, and partially restored the transcriptional response to oleic acid in the presence of insulin through JNK pathway. Taken together, these data open new perspectives to study the molecular mechanisms commonly dysregulated in mouse and human obesity at the level of lipogenesis linked to hypertrophy and adipogenesis linked to hyperplasia.
authors.affiliation: Lyon University; INSERM; UMR1060; INRA1397; CarMeN Laboratory; INSA; HCL ; Lyon, France.
authors.forename: E
authors.initials: E
authors.lastname: Berger
authors.affiliation: Laboratoire des Substituts Cutanés; Hôpital Edouard Herriot ; Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Héraud
authors.affiliation: Service de Chirurgie Plastique; Hôpital Edouard Herriot ; Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Mojallal
authors.affiliation: Laboratoire des Substituts Cutanés; Hôpital Edouard Herriot ; Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Lequeux
authors.affiliation: Lyon University; Center de Génétique et de Physiologie Moléculaire et Cellulaire (CGPhiMC); CNRS UMR5534 ; Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Weiss-Gayet
authors.affiliation: Laboratoire des Substituts Cutanés; Hôpital Edouard Herriot ; Lyon, France.
authors.forename: O
authors.initials: O
authors.lastname: Damour
authors.affiliation: Lyon University; INSERM; UMR1060; INRA1397; CarMeN Laboratory; INSA; HCL ; Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Géloën
keywords: (h)ASCs, (human)adipose stem cells; (h)dA, (human) adipocytes differentiated in vitro; ACSL1, Acyl-CoA synthetase long chain family member 1; AQP7, aquaporin 7; BSA, bovine serum albumin, lipid-free; CEBPA, CCAAT/enhancer binding protein (C/EBP) α; CIDEA &; CIDEC, cell death-inducing DFFA-like effectors a and c; COL1A1 &; COL1A3, Collagens 1 α; DMEM, Dulbecco's Modified Eagle's Medium; ECM, extracellular matrix; FABP1 and 4, fatty acid binding proteins 1 and 4; FAT/CD36, fatty acid translocase; FCS, foetal calf serum; FN1, fibronectin; GO, Gene Ontology; HSPG, heparan sulfate proteoglycans; IBMX, isobutylmethylxanthine; IL6, interleukin 6; JNK, Jun-NH2 kinase; LIPE, hormone-sensitive lipase; MMP9, matrix metallopeptidase 9; PBS, phosphate buffered saline; PLIN, perilipin; PPARG, peroxisome-proliferator receptor gamma; RT-qPCR, real-time quantitative polymerase chain reaction; RTCA, Real-time Cell Analyzer; TA, adipose tissue; TNFA, tumor necrosis factor α; adipogenesis; bFGF, basic fibroblast growth factor; bio-informatics; fatty acid; lipogenesis; obesity; real-time cell analysis; subunits 1 and 3