title: High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice.
abstract: Metabolic inflammation in adipose tissue and the liver is frequently observed as a result of diet-induced obesity in human and rodent studies. Although the adipose tissue and the liver are both prone to become chronically inflamed with prolonged obesity, their individual contribution to the development of metabolic inflammation remains speculative. Thus, we aimed to elucidate the sequence of inflammatory events in adipose and hepatic tissues to determine their contribution to the development of metabolic inflammation and insulin resistance (IR) in diet-induced obesity. To confirm our hypothesis that adipose tissue (AT) inflammation is initiated prior to hepatic inflammation, C57BL/6J male mice were fed a low-fat diet (LFD; 10% kcal fat) or high-fat diet (HFD; 45% kcal fat) for either 24, 40 or 52 weeks. Lipid accumulation and inflammation was measured in AT and liver. Glucose tolerance was assessed and plasma levels of glucose, insulin, leptin and adiponectin were measured at various time points throughout the study. With HFD, C57BL/6j mice developed a progressive obese phenotype, accompanied by IR at 24 and 40 weeks of HFD, but IR was attenuated after 52 weeks of HFD. AT inflammation was present after 24 weeks of HFD, as indicated by the increased presence of crown-like structures and up-regulation of pro-inflammatory genes Tnf, Il1β, Mcp1 and F4/80. As hepatic inflammation was not detected until 40 weeks of HFD, we show that AT inflammation is established prior to the development of hepatic inflammation. Thus, AT inflammation is likely to have a greater contribution to the development of IR compared to hepatic inflammation.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section Medical Biology, Groningen, The Netherlands.
authors.forename: Roel A
authors.initials: RA
authors.lastname: van der Heijden
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Section Molecular Genetics, Groningen, The Netherlands.|Radboud University Medical Center, Department of Physiology, Nijmegen, The Netherlands.
authors.forename: Fareeba
authors.initials: F
authors.lastname: Sheedfar
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors.forename: Martine C
authors.initials: MC
authors.lastname: Morrison
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Section Molecular Genetics, Groningen, The Netherlands.
authors.forename: Pascal P H
authors.initials: PP
authors.lastname: Hommelberg
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section Medical Biology, Groningen, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Kor
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Section Molecular Genetics, Groningen, The Netherlands.
authors.forename: Niels J
authors.initials: NJ
authors.lastname: Kloosterhuis
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Section Molecular Genetics, Groningen, The Netherlands.
authors.forename: Nanda
authors.initials: N
authors.lastname: Gruben
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Sameh A
authors.initials: SA
authors.lastname: Youssef
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Section Molecular Genetics, Groningen, The Netherlands.|Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section Medical Biology, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Section Molecular Genetics, Groningen, The Netherlands.
authors.forename: Debby P Y
authors.initials: DP
authors.lastname: Koonen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Section Medical Biology, Groningen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D059305:Diet, High-Fat; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
keywords: NASH; adipose tissue; inflammation; insulin resistance; liver; metabolic syndrome; obesity