title: Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes.
abstract: Fatty acid binding proteins (FABPs) are cytosolic fatty acid chaperones whose biological role and mechanisms of action are not well understood. Here, we developed mice with targeted mutations in two related adipocyte FABPs, aP2 and mal1, to resolve their role in systemic lipid, glucose, and energy metabolism. Mice lacking aP2 and mal1 exhibited a striking phenotype with strong protection from diet-induced obesity, insulin resistance, type 2 diabetes, and fatty liver disease. These mice have altered cellular and systemic lipid transport and composition, leading to enhanced insulin receptor signaling, enhanced muscle AMP-activated kinase (AMP-K) activity, and dramatically reduced liver stearoyl-CoA desaturase-1 (SCD-1) activity underlying their phenotype. Taken together with the previously reported strong protection against atherosclerosis, these results demonstrate that adipocyte/macrophage FABPs have a robust impact on multiple components of metabolic syndrome, integrating metabolic and inflammatory responses in mice and constituting a powerful target for the treatment of these diseases.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Maeda
authors.forename: Haiming
authors.initials: H
authors.lastname: Cao
authors.forename: Keita
authors.initials: K
authors.lastname: Kono
authors.forename: Cem Z
authors.initials: CZ
authors.lastname: Gorgun
authors.forename: Masato
authors.initials: M
authors.lastname: Furuhashi
authors.forename: Kadir T
authors.initials: KT
authors.lastname: Uysal
authors.forename: Qiong
authors.initials: Q
authors.lastname: Cao
authors.forename: Genichi
authors.initials: G
authors.lastname: Atsumi
authors.forename: Harry
authors.initials: H
authors.lastname: Malone
authors.forename: Bala
authors.initials: B
authors.lastname: Krishnan
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.forename: Rex A
authors.initials: RA
authors.lastname: Parker
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D015151:Immunoblotting; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D009765:Obesity / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D014280:Triglycerides; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D010100:Oxygen