Retinol‐binding Protein 4, Visceral Fat, and the Metabolic Syndrome: Effects of Weight Loss

Tschoner, Alexander; Sturm, Wolfgang; Engl, Julia; Kaser, Susanne; Laimer, Markus; Laimer, Elisabeth; Weiß, Helmut; Patsch, Josef R.; Ebenbichler, Christoph

doi:10.1038/oby.2008.391

Cited by 63 publications

(58 citation statements)

References 48 publications

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“…Therefore, these results imply that RBP 4 may be considered as a dynamic marker of negative energy balance, being reduced during weight loss when a negative energy balance threshold is reached, independently of the BMI of the individuals at a given time point. Moreover, there was no diff erence in the induced changes in circulating RBP 4 between patients undergoing gastric banding and gastric bypass [ 84 ] .…”

Section: Surgical Managementmentioning

confidence: 99%

The Metabolic Role of Retinol Binding Protein 4: An Update

Christou

Tselepis²,

Kiortsis

2011

Horm Metab Res

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reviews investigating thoroughly all the metabolic eff ects of RBP 4. In this context, this article reviews the major aspects of the possible metabolic actions of RBP 4 and attempts to elucidate any resting confusion on this matter. The literature search was based on PubMed listings up to 1 August 2011. Type 2 Diabetes and Insulin Resistance ▼ Relationship between RBP 4 and clinical and laboratory parameters of insulin resistance Circulating RBP 4 and expression of RBP 4 mRNA in abdominal adipose tissue are increased in subjects with type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT), compared to subjects with normal glucose tolerance (NGT) [ 5-7 ]. However, circulating RBP 4 and synthesis rates of RBP 4 appear to be lower in type 1 diabetes mellitus (T1DM) compared to normal, nondiabetic individuals [ 8-11 ]. Furthermore, circulating RBP 4 is higher in women with gestational diabetes mellitus compared to healthy pregnant women [ 12 , 13 ]. Moreover, in nonobese, normoglycemic subjects with at least one fi rst-degree relative with T2DM, serum RBP 4 levels correlate inversely with the glucose disposal rate (GDR), which is a

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Section: Surgical Managementmentioning

confidence: 99%

The Metabolic Role of Retinol Binding Protein 4: An Update

Christou

Tselepis²,

Kiortsis

2011

Horm Metab Res

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“…This may result from the use of different populations of human subjects or from methodological issues with RBP4 assays (18,32,64). Many studies also show that serum RBP4 levels correlate with other components of the metabolic syndrome in humans, including hypertension (47, 54, 64), dyslipidemia (41, 47, 64, 67), waist/hip ratio (31, 47, 64), cardiovascular disease (26), and intra-abdominal fat mass (9,31,36,56). Strong associations have been demonstrated in large-scale population studies in several ethnic backgrounds (38,47).…”

mentioning

confidence: 99%

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

Norseen

Hosooka

Hammarstedt

et al. 2012

Molecular and Cellular Biology

228

224

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dRetinol-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.O besity is a major risk factor for insulin resistance, which is a critical pathogenic factor in type 2 diabetes (50). Determination of the physiologic and cellular mechanisms linking obesity to type 2 diabetes could lead to development of new prevention and treatment approaches. Multiple mechanisms may contribute, including abnormal production of adipocyte-secreted proteins (adipokines) (1,15,29), infiltration of white adipose tissue (WAT) with proinflammatory macrophages (42), and aberrant lipid deposition in tissues such as muscle and liver (51). These mechanisms are not mutually exclusive. For example, adipokines can affect inflammation and lipid deposition in tissues (15).Serum retinol-binding protein 4 (RBP4) is an adipokine and is also secreted by liver. RBP4 levels are increased in obese and insulin-resistant humans and mouse models, and genetic or pharmacologic elevation of serum RBP4 causes insulin resistance in normal mice (19,31,65). Although many studies show strong correlations of serum RBP4 levels with obesity and the severity of insulin resistance (9,16,27,35), others do not (8,17,32,46), as reviewed in reference 32. This may result from the use of different populations of human subjects or from methodological issues with RBP4 assays (18,32,64). Many studies also show that serum RBP4 levels correlate with other components of the metabolic syndrome in humans, including hypertension (47, 54, 64), dyslipidemia (41, 47, 64, 67), waist/hip ratio (31...

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“…In addition to its well-established role as the major blood carrier of retinol, RBP4 has been implicated in the regulation of systemic insulin sensitivity [31,74,82,106]. Consistent with this view, increased circulating RBP4 concentrations have been reported in several metabolic complications such as obesity [5,6,31,33,47,72,99], insulin resistance [18,31,72,84,103], metabolic syndrome [5,35,83,104], polycystic ovary syndrome [32,98] and cardiovascular disease [35,104].…”

Section: Introductionmentioning

confidence: 52%