A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction.
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Moreno-Navarrete José María, Escoté Xavier, Ortega Francisco, Serino Matteo, Campbell Mark, Michalski Marie-Caroline, Laville Martine, Xifra Gemma, Luche Elodie, Domingo Pere, Sabater Mónica, Pardo Gerard, Waget Aurelie, Salvador Javier, Giralt Marta, Rodriguez-Hermosa Jose I, Camps Marta, Kolditz Catherine I, Viguerie Nathalie, Galitzky Jean, Decaunes Pauline, Ricart Wifredo, Frühbeck Gema, Villarroya Francesc, Mingrone Geltrude, Langin Dominique, Zorzano Antonio, Vidal Hubert, Vendrell Joan, Burcelin Remy, Vidal-Puig Antonio, Fernández-Real José Manuel
Аннотация
METHODS: LBP mRNA and LBP protein levels were analysed in AT from three cross-sectional (n = 210, n = 144 and n = 28) and three longitudinal (n = 8, n = 25, n = 20) human cohorts; in AT from genetically manipulated mice; in isolated adipocytes; and in human and murine cell lines. The effects of a high-fat diet and exposure to lipopolysaccharide (LPS) and peroxisome proliferator-activated receptor (PPAR)γ agonist were explored. Functional in vitro and ex vivo experiments were also performed.
RESULTS: LBP synthesis and release was demonstrated to increase with adipocyte differentiation in human and mouse AT, isolated adipocytes and human and mouse cell lines (Simpson-Golabi-Behmel syndrome [SGBS], human multipotent adipose-derived stem [hMAD] and 3T3-L1 cells). AT LBP expression was robustly associated with inflammatory markers and increased with metabolic deterioration and insulin resistance in two independent cross-sectional human cohorts. AT LBP also increased longitudinally with weight gain and excessive fat accretion in both humans and mice, and decreased with weight loss (in two other independent cohorts), in humans with acquired lipodystrophy, and after ex vivo exposure to PPARγ agonist. Inflammatory agents such as LPS and TNF-α led to increased AT LBP expression in vivo in mice and in vitro, while this effect was prevented in Cd14-knockout mice. Functionally, LBP knockdown using short hairpin (sh)RNA or anti-LBP antibody led to increases in markers of adipogenesis and decreased adipocyte inflammation in human adipocytes.
CONCLUSIONS/INTERPRETATION: Collectively, these findings suggest that LBP might have an essential role in inflammation- and obesity-associated AT dysfunction.