Adipocytokine orosomucoid integrates inflammatory and metabolic signals to preserve energy homeostasis by resolving immoderate inflammation.
Orosomucoid (ORM), also called alpha-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections. In this study, we reveal that Orm is induced selectively in the adipose tissue of obese mice to suppress excess inflammation that otherwise disturbs energy homeostasis. Adipose Orm levels were elevated by metabolic signals, including insulin, high glucose, and free fatty acid, as well as by the proinflammatory cytokine tumor necrosis factor-alpha, which is found in increased levels in the adipose tissue of morbid obese subjects. In both adipocytes and macrophages, ORM suppressed proinflammatory gene expression and pathways such as NF-kappaB and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-alpha-mediated lipolysis in adipocytes. Accordingly, ORM improved glucose and insulin tolerance in obese and diabetic db/db mice. Taken together, our results suggest that ORM integrates inflammatory and metabolic signals to modulate immune responses to protect adipose tissue from excessive inflammation and thereby from metabolic dysfunction.
Lee
Yun Sok
YS
Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea.
Choi
Jin Woo
JW
Hwang
Injae
I
Lee
Joo Won
JW
Lee
Jae Ho
JH
Kim
A Young
AY
Huh
Jin Young
JY
Koh
Young Jun
YJ
Koh
Gou Young
GY
Son
Hee Jung
HJ
Masuzaki
Hiroaki
H
Hotta
Kikuko
K
Alfadda
Assim A
AA
Kim
Jae Bum
JB
D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008820:Mice, Obese; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009961:Orosomucoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054392:Adipokines; D022762:CCAAT-Enhancer-Binding Proteins; D004041:Dietary Fats; D007328:Insulin; D016328:NF-kappa B; D009961:Orosomucoid; D051780:Sterol Regulatory Element Binding Protein 1; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases