title: Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism.
abstract: Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Blake J
authors.initials: BJ
authors.lastname: Cochran
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Liming
authors.initials: L
authors.lastname: Hou
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Anil Paul Chirackal
authors.initials: AP
authors.lastname: Manavalan
authors.affiliation: Division of Medicine, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Moore
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Tabet
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Afroza
authors.initials: A
authors.lastname: Sultana
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Luisa
authors.initials: L
authors.lastname: Cuesta Torres
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Shudi
authors.initials: S
authors.lastname: Tang
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Sudichhya
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Praween
authors.initials: P
authors.lastname: Senanayake
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Mili
authors.initials: M
authors.lastname: Patel
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Ryder
authors.affiliation: Biological Resource Imaging Laboratory, Mark Wainwright Analytical Centre, University of New South Wales Australia, Sydney, Australia.
authors.forename: Andre
authors.initials: A
authors.lastname: Bongers
authors.affiliation: Aix-Marseille Université, UMR_S1062, UMR_A1260, Nutrition, Obésité et Risque Thrombotique, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Maraninchi
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, University of New South Wales Australia, Sydney, Australia.
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Wasinger
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY.
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia.|Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.affiliation: Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales Australia, Sydney, Australia k.rye@unsw.edu.au karye@ozemail.com.au.|Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000172:deficiency / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000172:deficiency / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism*; D064429:Fatty Acid Synthases; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D008279:Magnetic Resonance Imaging; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D016133:Polymerase Chain Reaction
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D002784:Cholesterol; D064429:Fatty Acid Synthases; D005947:Glucose; D006003:Glycogen; D007328:Insulin; D019344:Lactic Acid; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse