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

Abstract

Orosomucoid (ORM), also called ␣-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-␣, 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-B and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-␣-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.

Orosomucoid Serum Concentrations and Fat Depot-Specific mRNA and Protein Expression in Humans

“…A previous study involving morbidly obese females and moderately obese males also showed that ORM protein concentrations were doubled compared to lean controls (Benedek et al, 1983;1984). We also showed previously that serum ORM levels were significantly elevated in obese people as compared to healthy people (Lee et al, 2010). The correlation of circulating ORM levels with BMI and percentage body fat suggests that adipose tissue may be a contributing source for circulating ORM.…”

“…ORM mRNA expression in adipose tissue was elevated in obese mice with increasing ORM plasma levels, and its expression was augmented by a high fat diet. In adipocytes, ORM suppressed proinflammatory gene expression and pathways such as IKK/NF-κB and mitogen-activated protein kinase (MAPK) signaling and reactive oxygen species (ROS) generation (Lee et al, 2010). These results suggest that ORM modulates immune responses to protect adipose tissue from the effects of excessive inflammation and metabolic dysfunction.…”

“…In contrast, expression of liver ORM was induced by LPS, but not by HFD. These results suggest that adipose ORM, in contrast to liver ORM, is modulated by distinct mechanisms upon exposure to pathophysiological conditions (Lee et al, 2010).…”

“…Furthermore, ORM suppressed TNF-α gene expression and generation of ROS in adipocytes and macrophages through the suppression of IKK/NF-κB and MAPK pathways. Induction of a high circulating level of ORM in db/db mice by continuous infusion of purified ORM protein reduced the expression of inflammatory cytokine genes, namely TNF-α and IL-6 (Lee et al, 2010). Due to the association of ORM with these inflammatory cytokines, it is possible that ORM plays a role in limiting inflammation in human adipose tissue.…”

The Answer to Why Some Are Obese but Healthy?!

“…Its secretion from the adipocytes markedly increases in inflammatory and metabolic stress conditions and also by TNF-, insulin, glucose and free fatty acids [59]. It is believed that there is a positive correlation between circulating orosomucoid levels and BMI and body fat mass rather than the metabolic status of the individual [58].…”