title: Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans.
abstract: Adipocyte lipopolysaccharide-binding protein (LBP) biosynthesis is associated with obesity-induced adipose tissue dysfunction. Our purpose was to study the role of LBP in regulating the browning of adipose tissue.
  
  
  
  Adult mice were maintained at 4°C for 3 weeks or treated with the β3-adrenergic agonist, CL316,243, for 1 week to induce the browning of white fat. Precursor cells from brown and white adipose tissues were cultured under differentiation-inducing conditions to yield brown and beige/brite adipocytes, respectively. In vitro, Lbp was knocked down in 3T3-L1 adipocytes, and cells were treated with recombinant LBP or co-cultured in transwells with control 3T3-L1 adipocytes. Wild-type and Lbp-null mice, fed a standard or high fat diet (HFD) for 15 weeks, were also used in investigations. In humans, subcutaneous and visceral adipose tissue samples were obtained from a cohort of morbidly obese participants.
  
  
  
  The induction of white fat browning by exposure of mice to cold or CL316,243 treatment was strongly associated with decreased Lbp mRNA expression in white adipose tissue. The acquisition of the beige/brite phenotype in cultured cells was associated with downregulation of Lbp. Moreover, silencing of Lbp induced the expression of brown fat-related genes in adipocytes, whereas LBP treatment reversed this effect. Lbp-null mice exhibited the spontaneous induction of subcutaneous adipose tissue browning, as evidenced by a remarkable increase in Ucp1 and Dio2 gene expression and the appearance of multivacuolar adipocyte clusters. The amount of brown adipose tissue, and brown adipose tissue activity were also increased in Lbp-null mice. These changes were associated with decreased weight gain in Lbp-null mice and protection against HFD-induced inflammatory responses, as shown by reduced IL-6 levels. However, rather than improving glucose homeostasis, these effects led to glucose intolerance and insulin resistance.
  
  
  
  LBP is identified as a negative regulator of the browning process, which is likely to contribute to the obesity-promoting action of LBP. The deleterious metabolic effects of LBP deletion are compatible with the concept that the appropriate regulation of inflammatory pathways is necessary for a healthy systemic metabolic profile, regardless of body weight regulation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Catalonia, Spain.|The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Gavaldà-Navarro
authors.affiliation: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain.|Section of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona "Dr Josep Trueta", Girona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Catalonia, Spain.|The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Quesada-López
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Catalonia, Spain.|The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cairó
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Catalonia, Spain.|The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Giralt
authors.affiliation: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain.|Section of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Hospital of Girona "Dr Josep Trueta", Girona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Real
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Catalonia, Spain. fvillarroya@ub.edu.|The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain. fvillarroya@ub.edu.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain. fvillarroya@ub.edu.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain, . fvillarroya@ub.edu.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
mesh_terms: D041721:3T3-L1 Cells; D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D059305:Diet, High-Fat / Q000009:adverse effects; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D005346:Fibroblast Growth Factors; D007453:Iodide Peroxidase; D008562:Membrane Glycoproteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056566:Sirtuin 3; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II; D000099231:Lipopolysaccharide-Binding Protein; C525046:Sirt3 protein, mouse; C000604372:Ucp1 protein, mouse; C414620:fibroblast growth factor 21
keywords: Brown adipose tissue; Browning; High-fat diet; Lipopolysaccharide-binding protein; Obesity