Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes.
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.
Maeda
Kazuhisa
K
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Cao
Haiming
H
Kono
Keita
K
Gorgun
Cem Z
CZ
Furuhashi
Masato
M
Uysal
Kadir T
KT
Cao
Qiong
Q
Atsumi
Genichi
G
Malone
Harry
H
Krishnan
Bala
B
Minokoshi
Yasuhiko
Y
Kahn
Barbara B
BB
Parker
Rex A
RA
Hotamisligil
Gökhan S
GS
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
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