title: Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice.
abstract: Osteopontin (OPN) is a multifunctional extracellular matrix (ECM) protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD) using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT) and liver in wild type (WT) mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver.
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Andoni
authors.initials: A
authors.lastname: Lancha
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Rodríguez
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Catalán
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Becerril
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Neira
authors.initials: N
authors.lastname: Sáinz
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ramírez
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain; Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Burrell
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Salvador
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Frühbeck
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gómez-Ambrosi
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D000354:Africa, Western; D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000502:physiology; D001835:Body Weight; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D005234:Fatty Liver / Q000235:genetics*; D005355:Fibrosis; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009765:Obesity / Q000235:genetics*; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics*; D018384:Oxidative Stress / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D017392:Thiobarbituric Acid Reactive Substances
chemical_list: D017392:Thiobarbituric Acid Reactive Substances; D053495:Osteopontin; D003094:Collagen