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BACKGROUND AND PURPOSERetinol-binding protein 4 (RBP4) is an adipocyte-secreted hormone proposed to link obesity with insulin resistance. However, the role of RBP4 in cardiovascular complications is yet to be fully understood. The present study is aimed to decipher the association between RBP4 with pro-inflammatory cytokines and low-density lipoprotein (LDL) cholesterol in diet-induced obese and hyperlipidaemic mice. To understand the correlation, rimonabant, an anti-obesity drug, has been used to relieve the atherosclerotic predisposition. EXPERIMENTAL APPROACHAdipose and/or aortic tissue expressions of RBP4, pro-inflammatory cytokine genes and circulating LDL levels were measured in high fat (HF)-fed female C57BL/6 and high cholesterol (HC)-fed apolipoprotein E3 (ApoE3) Leiden mice. KEY RESULTSMice fed a HF diet had a significantly increased adipose expression of RBP4, TNF-a and monocyte chemoattractant protein 1 (MCP-1) and down-regulated adiponectin mRNA levels. A significant increase in aortic RBP4 and MCP-1 expression and circulating levels of LDL and C-reactive protein (CRP) was found in the ApoE3 mice fed a HC diet. Interestingly, rimonabant treatment lowered the elevated aortic RBP4, MCP-1 expressions and significantly reduced the serum levels of LDL, CRP, RBP4 and MCP-1. CONCLUSION AND IMPLICATIONSOur results indicate that RBP4 is positively associated with markers of inflammation in obese and pro-atherogenic conditions and could play a role in a predisposition to atherosclerosis. Furthermore, our results indicate that rimonabant may improve vascular function by modulating RBP4 along with pro-inflammatory cytokines.

Agonists of the thiazolidinedione class of peroxisome proliferator-activated receptor-γ exhibit both insulin-sensitizing and anti-inflammatory effects. We hypothesized that pioglitazone might be able to exert its anti-inflammatory properties at a lower dose than that required for its insulin-sensitizing effect. In order to investigate this hypothesis, we evaluated the effects of pioglitazone on inflammatory as well as metabolic biomarkers in serum and white adipose tissue (WAT) at 2 different doses. Female db/db mice were treated orally with therapeutic (30 mg/kg) and subtherapeutic (3 mg/kg) doses of pioglitazone for 14 days followed by an oral glucose tolerance test. Other parameters measured were inflammatory markers such as tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and metabolic biomarkers in serum (insulin, glucose and adiponectin). Moreover, adiponectin, fatty acid-binding protein (aP2) and lipoprotein lipase (LPL) mRNA expression in WAT were determined by real-time PCR. A subtherapeutic dose of pioglitazone significantly suppresses the expression of TNF-α and IL-6 mRNA in WAT, but does not alter the serum glucose, insulin and WAT expression of adiponectin, adipocyte aP2 and LPL. A therapeutic dose of pioglitazone improves insulin sensitivity, enhances LPL, aP2 and adiponectin expression, and also suppresses TNF-α and IL-6 expression. In conclusion, the current study indicates that the anti-inflammatory effect of pioglitazone is produced at a subtherapeutic dose, which is considerably lower than the dose needed to produce any desired metabolic effects. Anti-inflammatory effects of pioglitazone may precede its insulin-sensitizing effects in db/db mice.

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