Regulatory SNP in the <i>RBP4</i> Gene Modified the Expression in Adipocytes and Associated With BMI

Munkhtulga, Lkhagvasuren; Nagashima, Shuichi; Nakayama, Kazuhiro; Utsumi, Nanami; Yanagisawa, Yoshiko; Gotoh, Tadao; Omi, Toshinori; Kumada, Maki; Zolzaya, Khadbaatar; Lkhagvasuren, Tserenkhuu; Kagawa, Yasuo; Fujiwara, Hiroyuki; Hosoya, Yoshinori; Hyodo, Masanobu; Horie, Hisanaga; Kojima, Masayasu; Ishibashi, Shun; Iwamoto, Sadahiko

doi:10.1038/oby.2009.358

Cited by 56 publications

(54 citation statements)

References 37 publications

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“…This appears to be more than a spurious correlation, since recent studies have demonstrated that RBP4 is an adipokine (adipose-derived cytokine) with retinoid-independent, proinflammatory activity that contributes to the development of insulin resistance (13,(19)(20)(21). Moreover, a human single nucleotide polymorphism that increases RBP4 promoter activity confers a 2-fold increase for the risk of type 2 diabetes (22,23).…”

Section: S Erum Retinol-binding Protein 4 (Rbp4) Is the Sole Specificmentioning

confidence: 99%

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Otalora

Martin

et al. 2015

Molecular and Cellular Biology

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Serum retinol-binding protein 4 (RBP4) is the sole specific transport protein for retinol in the blood, but it is also an adipokine with retinol-independent, proinflammatory activity associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Moreover, two separate studies reported that patients with proliferative diabetic retinopathy have increased serum RBP4 levels compared to patients with mild or no retinopathy, yet the effect of increased levels of RBP4 on the retina has not been studied. Here we show that transgenic mice overexpressing RBP4 (RBP4-Tg mice) develop progressive retinal degeneration, characterized by photoreceptor ribbon synapse deficiency and subsequent bipolar cell loss. Ocular retinoid and bisretinoid levels are normal in RBP4-Tg mice, demonstrating that a retinoid-independent mechanism underlies retinal degeneration. Increased expression of pro-interleukin-18 (pro-IL-18) mRNA and activated IL-18 protein and early-onset microglia activation in the retina suggest that retinal degeneration is driven by a proinflammatory mechanism. Neither chronic systemic metabolic disease nor other retinal insults are required for RBP4 elevation to promote retinal neurodegeneration, since RBP4-Tg mice do not have coincident retinal vascular pathology, obesity, dyslipidemia, or hyperglycemia. These findings suggest that elevation of serum RBP4 levels could be a risk factor for retinal damage and vision loss in nondiabetic as well as diabetic patients. S erum retinol-binding protein 4 (RBP4) is the sole specific transport protein for vitamin A (retinol) in the blood (1-4).The eye is the organ most dependent on the RBP4-mediated delivery of retinol to maintain optimal function, as RBP4 loss of function in either mice or humans impairs retinal function, leading to visual impairment, while other organ systems remain intact (5-7). However, in the past decade numerous clinical studies have linked increased serum levels of RBP4 to disease, including obesity (8, 9), insulin resistance (8-13), type 2 diabetes (9, 13), and cardiovascular disease (hypertension, atherosclerosis, stroke) (14-18). This appears to be more than a spurious correlation, since recent studies have demonstrated that RBP4 is an adipokine (adipose-derived cytokine) with retinoid-independent, proinflammatory activity that contributes to the development of insulin resistance (13,(19)(20)(21). Moreover, a human single nucleotide polymorphism that increases RBP4 promoter activity confers a 2-fold increase for the risk of type 2 diabetes (22, 23).Several studies have provided mechanistic insights into RBP4-induced insulin resistance. Mice with genetic or pharmacologic elevation of RBP4 levels develop insulin resistance (13), whereas lowering of RBP4 levels improves insulin sensitivity in mice (13,24). RBP4 inhibits insulin signaling in adipocytes indirectly by activating proinflammatory cytokine production in macrophages through retinol-independent and Toll-like receptor 4 (TLR4)-and c-Jun N-terminal kinase (JNK)-dependent ...

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Section: S Erum Retinol-binding Protein 4 (Rbp4) Is the Sole Specificmentioning

confidence: 99%

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Otalora

Martin

et al. 2015

Molecular and Cellular Biology

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“…Two SNPs (SNP (risk allele) rs10882283(G) and rs10882273(C)) are associated with increased BMI and waist-to-hip ratio (33). Regulatory RBP4 SNP (SNP (risk allele) rs3758539(A)) resulting in overexpression of RBP4 and increased susceptibility for obesity, as a consequence of increased adipogenesis, has been reported (34). In addition, a higher visceral RBP4 mRNA expression has been reported in diabetes risk RBP4 haplotype carriers (SNP (risk allele) rs3758539(G), c.248C44TOC, rs12265684(G), and rs10882273(C)) (33).…”

Section: Characteristics Of Rbp4mentioning

confidence: 99%

RBP4: a controversial adipokine

Kotnik

Fischer‐Posovszky

Wabitsch

2011

European Journal of Endocrinology

211

165

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Adipose tissue is an endocrine organ secreting biologically active factors called adipokines that act on both local and distant tissues. Adipokines have an important role in the development of obesity-related comorbidities not only in adults but also in children and adolescents. Retinol binding protein 4 (RBP4) is a recently identified adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. However, data, especially resulting from the clinical studies, are conflicting. In this review, we summarize up-to-date knowledge on RBP4's role in obesity, development of insulin resistance, and T2D. Special attention is given to studies on children and adolescents. We also discuss the role of possible confounding factors that should be taken into account when critically evaluating published studies or planning new studies on this exciting adipokine.

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“…The tissues were immediately transported to the laboratory in ice-cold saline, frozen in liquid nitrogen within 10 min of collection, and stored at 80 until the experiment, as reported previously 31) .…”

Section: Biopsy Of Adipose Tissuesmentioning

confidence: 99%

Depot-Specific Expression of Lipolytic Genes in Human Adipose Tissues

Nagashima¹,

Yagyu²,

Takahashi³

et al. 2011

JAT

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Aim: Adipocyte lipolysis is mediated by a family of triglyceride (TG) lipases consisting of hormonesensitive lipase (LIPE), adipose triglyceride lipase (PNPLA2) and carboxylesterase 1 (CES1); however, little is known about the relationship between the expression of each gene in different depots and TG lipase activity or obesity Method: We measured both mRNA expression levels of the lipolytic enzymes (LIPE, PNPLA2 and CES1) and TG lipase activities of biopsy samples obtained from subcutaneous, omental and mesenteric adipose tissues of 34 patients who underwent abdominal surgery. The results were correlated with clinical parameters: adiposity measures, parameters for insulin resistance and plasma lipid levels. Results: PNPLA2 mRNA levels were slightly higher in omental fat than subcutaneous fat. Cytosolic TG lipase activities were positively correlated with the mRNA levels of CES1 in subcutaneous fat and mesenteric fat, while they were correlated with those of PNPLA2 in omental fat. The mRNA levels of LIPE were negatively correlated with various measures of adiposity in subcutaneous fat. The mRNA levels of CES1 were positively correlated with various measures of adiposity, particularly those estimated by CT in the three depots; they were also positively correlated with plasma LDL-cholesterol levels in omental fat. In contrast, the mRNA levels of PNPLA2 were not significantly associated with adiposity. Conclusions: The positive correlations of the expression of CES1 with cytosolic TG lipase activities as well as with adiposity suggest that CES1 is involved in lipolysis, thereby contributing to the development of obesity-associated phenotypes. On the other hand, the expression of LIPE is negatively correlated with adiposity. These distinct regulatory patterns of lipolytic genes may underlie the complex phenotypes associated with human obesity.

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Regulatory SNP in the RBP4 Gene Modified the Expression in Adipocytes and Associated With BMI

Cited by 56 publications

References 37 publications

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

RBP4: a controversial adipokine

Depot-Specific Expression of Lipolytic Genes in Human Adipose Tissues

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