Retinol-Binding Protein 4 Inhibits Insulin Signaling in Adipocytes by Inducing Proinflammatory Cytokines in Macrophages through a c-Jun N-Terminal Kinase- and Toll-Like Receptor 4-Dependent and Retinol-Independent Mechanism

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 03/2012; 32(10):2010-9. DOI: 10.1128/MCB.06193-11
Source: PubMed


Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood, is secreted from adipocytes and liver. Serum RBP4 levels correlate highly with insulin resistance, other metabolic syndrome factors, and cardiovascular disease. Elevated serum RBP4 causes insulin resistance, but the molecular mechanisms are unknown. Here we show that RBP4 induces expression of proinflammatory cytokines in mouse and human macrophages and thereby indirectly inhibits insulin signaling in cocultured adipocytes. This occurs through activation of c-Jun N-terminal protein kinase (JNK) and Toll-like receptor 4 (TLR4) pathways independent of the RBP4 receptor, STRA6. RBP4 effects are markedly attenuated in JNK1-/- JNK2-/- macrophages and TLR4-/- macrophages. Because RBP4 is a retinol-binding protein, we investigated whether these effects are retinol dependent. Unexpectedly, retinol-free RBP4 (apo-RBP4) is as potent as retinol-bound RBP4 (holo-RBP4) in inducing proinflammatory cytokines in macrophages. Apo-RBP4 is likely to be physiologically significant since RBP4/retinol ratios are increased in serum of lean and obese insulin-resistant humans compared to ratios in insulin-sensitive humans, indicating that higher apo-RBP4 is associated with insulin resistance independent of obesity. Thus, RBP4 may cause insulin resistance by contributing to the development of an inflammatory state in adipose tissue through activation of proinflammatory cytokines in macrophages. This process reveals a novel JNK- and TLR4-dependent and retinol- and STRA6-independent mechanism of action for RBP4.

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    • "RBP4 levels in serum and AT strongly correlate with subclinical inflammation, including pro-inflammatory cytokine levels. Indeed, RBP4 impairs insulin signaling in adipocytes indirectly by the activation of macrophages via Toll-like receptor 4 (TLR4) and c-Jun N-terminal protein kinase (JNK) pathways leading to Th1 cytochines production [7] [8] [9]. In addition, the RBP4/retinol complex stimulates JAK2/STAT5 signaling and expression of suppressor of cytokine signaling 3, which has also been implicated in insulin resistance via the plasma membrane protein called stimulated by retinoic acid 6 (STRA6). "
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    ABSTRACT: Obesity, insulin resistance, metabolic syndrome and type 2 diabetes have reached epidemic proportions, from here the term: diabesity. Vitamin A is delivered by a specific binding protein called retinol-binding protein 4 (RBP4) a soluble protein, emerging to have a role in insulin resistance, the major cause of diabetes highly associated with adipose tissue inflammation and obesity with action. RBP4, interacts with two receptors, the Toll-like receptor 4 (TLR4) and the plasma membrane protein called stimulated by retinoic acid 6 (STRA6) leading to the activation of c-Jun N-terminal protein kinase (JNK) pathways and JAK2/STAT5 cascade, respectively. Both mechanism sustain insulin resistance. In effect, ablation of STRA6 protects mice from RBP4-induced suppression of insulin signaling. In addition, mice harboring deletion of a specific chaperon for retinol, show infiltration of α-cells in the core of pancreatic islets, where usually only β-cells reside, showing a pre-diabetic like phenotype. Not only proteins in vitamin A shuttle and signaling are emerging in diabesity, recently the discovery of 9cis retinoic acid (9cRA) having effects in controlling glucose levels opened a new scenario. So far, only pancreas β-cells have been shown to synthesize it, and high levels of 9cRA correlate with obesity mice models. In this article, we summarize the recent literature present on this topic raising the hypothesis.
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    • "In addition to its effects on adipogenesis, RBP4 impairs macrophage secretory function. Macrophages challenged with apo-RBP4 or holo-RBP4 express increased levels of MCP1, IL-6 and TNF-a, which was independent of retinol and the RBP4 receptor STRA6 (Norseen et al. 2012). In conclusion, the adipokine RBP4 may contribute to the development of metabolic dysfunction by impairing adipocyte differentiation and increasing secretion of pro-inflammatory cytokines by macrophages. "
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    ABSTRACT: The discovery of adipokines has revealed adipose tissue as a central node in the inter-organ crosstalk network, which mediates the regulation of multiple organs and tissues. Adipose tissue is a true endocrine organ that produces and secretes a wide range of mediators regulating adipose tissue function in an auto-/paracrine manner and important distant targets like the liver, skeletal muscle, the pancreas and the cardiovascular system. In metabolic disorders such as obesity, enlargement of adipocytes leads to adipose tissue dysfunction and a shift in the secretory profile with an increased release of pro-inflammatory adipokines. Adipose tissue dysfunction has a central role in the development of insulin resistance, type 2 diabetes and cardiovascular diseases. Besides the well-acknowledged role of adipokines in metabolic diseases, and the increasing number of adipokines being discovered in the last years, the mechanisms underlying the release of many adipokines from adipose tissue remain largely unknown. In order to combat metabolic diseases, it is crucial to better understand how adipokines can modulate adipose tissue growth and function. Therefore, we will focus on adipokines with a prominent role in auto-/paracrine crosstalk within the adipose tissue such as RBP4, HO-1, WISP2, SFRPs and chemerin. In order to depict the endocrine crosstalk between adipose tissue with skeletal muscle, the cardiovascular system and the pancreas, we will report the main findings regarding the direct effects of adiponectin, leptin, DPP4 and visfatin on skeletal muscle insulin resistance, cardiovascular function and β-cell growth and function. This article is protected by copyright. All rights reserved.
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    • "This may have been affected by therapy (for example, insulin, glucose and catecholamine infusions). In addition, AECOPD patients reach an advanced state of inflammation where RBP4 is negligible in insulin resistance [25]. "
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    ABSTRACT: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are thought to be associated with increased mortality in elderly patients. Low retinol-binding protein-4 (RBP4) is associated with a high risk of respiratory infections in the general population. Therefore, we hypothesized that low RBP4 levels are associated with an increased risk of AECOPD and can be used as a biomarker for AECOPD in elderly patients. Enzyme-linked immunosorbent assays were used to assess RBP4 levels in elderly with AECOPD within the first 24 hours after intensive care unit admission. Forty-six elderly patients with stable COPD in outpatient clinics and 50 healthy elderly persons who had physical examinations as outpatients were controls. In AECOPD patients, RBP4 levels were lower than those in stable COPD patients and healthy controls (59.7 vs 91.2 and 113.6 mg/L, p < 0.001). RBP4 levels were decreased by 30.6% in non-survivors compared with survivors (51.5 vs 74.2 mg/L, p < 0.001). A higher Acute Physiology and Chronic Health Enquiry II (APACHE II) score and Simplified Acute Physiology score (SAPS II) were associated with lower RBP4 levels (r = -0.692, p = 0.024 and r = -0.670, p = 0.015, respectively). RBP4 was positively correlated with creatinine and body mass index, and negatively correlated with C-reactive protein and Global Initiative for Chronic Obstructive Lung Disease stage. Multivariate logistic regression showed that RBP4 was an independent mortality predictor of AECOPD (odds ratio: 0.926, p = 0.007). Analysis of the area under the receiver operating characteristic (AUC) curve showed that RBP4 showed good discrimination (AUC: 0.88; 95% confidence interval: 0.78--0.94; p = 0.008) in predicting mortality. RBP4 improved the prognostic accuracy of mortality for the APACHE II and SAPS II scores. Serum RBP4 levels are significantly reduced in elderly AECOPD patients. RBP4 might be a good predictive biomarker for mortality in elderly AECOPD patients in the intensive care unit.
    Journal of Inflammation 10/2013; 10(1):31. DOI:10.1186/1476-9255-10-31 · 2.02 Impact Factor
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