Adipocytokine Orosomucoid Integrates Inflammatory and Metabolic Signals to Preserve Energy Homeostasis by Resolving Immoderate Inflammation

Yun Sok Lee,Jin Woo Choi,Injae Hwang,Joo Won Lee,Jae Ho Lee,A Young Kim,Jin Young Huh,Young Jun Koh,Gou Young Koh,Hee Jung Son,Hiroaki Masuzaki,Kikuko Hotta,Assim A Alfadda,Jae Bum Kim

doi:10.1074/jbc.m109.085464

Abstract

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.

Highlights

Medicine, Samsung Medical Center, Seoul 135-710, Korea, the **Second Department of Internal Medicine, Graduate School of Medicine, University of the Ryukus, Okinawa 903-0215, Japan, the ‡‡SNP Research Center, RIKEN, Yokohama, Kanagawa 230-0045, Japan, the §§Obesity Research Center and Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia, and the ¶¶Department of Biophysics and Chemical Biology, Seoul National University, Orosomucoid (ORM), called ␣-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections
Accumulating evidence has suggested that the induction of inflammatory gene expression in the adipose tissue of obese subjects is associated with an increase of macrophage infiltration into the adipose tissue [7,8,9]
Orm Is Selectively Induced in the Fat Tissues of Obese and/or Diabetic Mice—In an attempt to identify novel adipocytokines, we analyzed gene expression profiles in 3T3-L1 preadipocytes and adipocytes, as well as in the fat tissues and plasma of normal and obese/diabetic mice by using surface-enhanced laser desorption ionization-time-of-flight mass spectrometry combined with RNA microarray analysis

Summary

The abbreviations used are

TNF␣, tumor necrosis factor-␣; ORM, orosomucoid; MAPK, mitogen-activated protein kinase; DMEM, Dulbecco’s modified Eagle’s medium; PBS, phosphate-buffered saline; Q-PCR, quantitative PCR; siRNA, small interfering RNA; JNK, c-Jun N-terminal kinase; ROS, reactive oxygen species; ERK, extracellular signal-regulated kinase; SVC, stromal vascular cell; TRITC, tetramethylrhodamine isothiocyanate; IKK, I␬B kinase; FFA, free fatty acid; LPS, lipopolysaccharide; HFD, high fat diet; DIO, diet-induced obese; IL, interleukin. Protective Roles of ORM against Insulin Resistance macrophages to produce more proinflammatory cytokines [4] This reciprocal activation between adipocytes and macrophages forms a vicious cycle to potentiate proinflammatory responses in the adipose tissue of obese subjects, concomitant with the dysregulation of the adipocytokine genes. Fatspecific ablation of the macrophage chemoattractant protein-1 (MCP-1), a critical chemokine for macrophage infiltration into inflamed tissues, protects mice from high fat diet-induced insulin resistance; MCP-1 overexpression causes insulin resistance in mice [11] This suggests that adipose tissue macrophages mediate local inflammation and eventually influence the development of metabolic disturbances. We prove that ORM is induced in response to both metabolic and inflammatory signals in the adipose tissue of obese mice to protect them from severe inflammation, unless there is serious disturbance in glucose and lipid homeostasis, which can eventually lead to systemic metabolic complications. We suggest that ORM is the protein that coordinates metabolic homeostasis in regulation of both energy metabolism and inflammation

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION