title: Mice Lacking beta2-Integrin Function Remain Glucose Tolerant in Spite of Insulin Resistance, Neutrophil Infiltration and Inflammation.
abstract: Beta2-integrins are important in leukocyte trafficking and function, and are regulated through the binding of cytoplasmic proteins, such as kindlin-3, to their intracellular domain. Here, we investigate the involvement of beta2-integrins in the regulation of metabolic disease using mice where the kindlin-3 binding site in the beta2-integrin cytoplasmic tail has been mutated (TTT/AAA-beta2-integrin knock-in (KI) mice), leading to expressed but dysfunctional beta2-integrins and significant neutrophilia in vivo. Beta2-integrin KI mice fed on a high fat diet showed normal weight gain, and normal accumulation of macrophages and lymphocytes in white adipose tissue (WAT) and liver, but increased neutrophil numbers especially in WAT. In addition, beta2-integrin KI mice fed on a high fat diet showed significantly increased peripheral insulin resistance in response to high-fat feeding. However, this was associated with improved glucose disposal following glucose load. Interestingly, beta2-integrin KI neutrophils produced more elastase in vitro, in response to stimulation. Beta2-integrin KI mice displayed variability of tissue inflammatory status, with liver and WAT exhibiting little or no difference in inflammation compared to high fat fed controls, whereas skeletal muscle demonstrated a raised inflammatory profile in association with higher elastase levels and diminished signalling through the IRS1-PKB pathway. In conclusion, although expression of dysfunctional beta2-integrins increased neutrophil production and infiltration into tissue, skeletal muscle was the most affected tissue exhibiting evidence of higher neutrophil activity and insulin resistance. Thus, beta2-integrins modulate glucose homeostasis during high fat feeding predominantly through actions on skeletal muscle to affect metabolic phenotype in vivo.
authors.affiliation: Divison of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Meakin
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Vicky L
authors.initials: VL
authors.lastname: Morrison
authors.affiliation: Divison of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Claire C
authors.initials: CC
authors.lastname: Sneddon
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Savinko
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Liisa
authors.initials: L
authors.lastname: Uotila
authors.affiliation: Divison of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Jalicy
authors.affiliation: Divison of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Gabriel
authors.affiliation: Divison of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.affiliation: Divison of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Michael L J
authors.initials: ML
authors.lastname: Ashford
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Susanna C
authors.initials: SC
authors.lastname: Fagerholm
mesh_terms: D052436:Adipose Tissue, White / Q000276:immunology; D000818:Animals; D001665:Binding Sites; D018821:CD18 Antigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D059305:Diet, High-Fat; D007333:Insulin Resistance; D008099:Liver / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009154:Mutation; D020556:Neutrophil Infiltration; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D018821:CD18 Antigens