Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

Yang, Qin; Graham, Timothy E.; Mody, Nimesh; Preitner, Frédéric; Peroni, Odile D.; Zabolotny, Janice M.; Kotani, Ko; Quadro, Loredana; Kahn, Barbara B.

doi:10.1038/nature03711

Cited by 1,860 publications

(2,253 citation statements)

References 45 publications

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“…33). Indeed, in the present study not only plasma TNF␣ levels but also RBP4 plasma concentration as well as phosphorylation status of AKT in the liver, all being parameters indicating insulin resistance, [34][35][36] were markedly altered in mice chronically fed fructose. Again, a similar effect of fructose feeding was not found in TLR-4 mutant mice.…”

Section: Discussionsupporting

confidence: 46%

Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice†

et al. 2009

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A link between dietary fructose intake, gut-derived endotoxemia, and nonalcoholic fatty liver disease (NAFLD) has been suggested by the results of human and animal studies. To further investigate the role of gut-derived endotoxin in the onset of fructose-induced NAFLD, Toll-like receptor (TLR-) 4-mutant (C3H/HeJ) mice and wildtype (C3H/HouJ) mice were either fed plain water or water enriched with 30% fructose for 8 weeks. Hepatic steatosis, plasma alanine aminotransferase (ALT), and markers of insulin resistance as well as portal endotoxin levels were determined. Hepatic levels of myeloid differentiation factor 88 (MyD88), interferon regulatory factor (IRF) 3 and 7, and tumor necrosis factor alpha (TNF␣) as well as markers of lipid peroxidation were assessed. Chronic intake of 30% fructose solution caused a significant increase in hepatic steatosis and plasma ALT levels in wildtype animals in comparison to water controls. In fructose-fed TLR-4 mutant mice, hepatic triglyceride accumulation was significantly reduced by Ϸ40% in comparison to fructose-fed wildtype mice and plasma ALT levels were at the level of water-fed controls. No difference in portal endotoxin concentration between fructose-fed wildtype and TLR-4-mutant animals was detected. In contrast, hepatic lipid peroxidation, MyD88, and TNF␣ levels were significantly decreased in fructose-fed TLR-4-mutant mice in comparison to fructose-fed wildtype mice, whereas IRF3 and IRF7 expression remained unchanged. Markers of insulin resistance (e.g., plasma TNF␣, retinol binding protein 4, and hepatic phospho-AKT) were only altered in fructose-fed wildtype animals. Conclusion: Taken together, these data further support the hypothesis that in mice the onset of fructose-induced NAFLD is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells.

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Section: Discussionsupporting

confidence: 46%

Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice†

et al. 2009

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“…Furthermore, in vitro studies demonstrated that retinol-RBP4 complex, but not apo-RBP, binds to TTR (3). In tune with these results, fenretinide, a drug that competes with retinol for binding to RBP4, inhibits its interaction with TTR and increases its renal clearance (3,5). Interestingly, knockouts of either RBP4 or TTR are viable, suggesting the existence of efficient compensatory mechanisms for the transport of retinol and thyroid hormones (3,4).…”

Section: Role Of Rbp4 and Ttr In Vitamin A Metabolismmentioning

confidence: 88%

“…The expression of RBP4 mRNA and protein was demonstrated in several extrahepatic tissues including adipocytes (3,5). Moreover, in mice lacking lecithin:-retinol acyltransferase, large amount of retinyl esters remain in the adipose tissue that are mobilized during dietary retinoid insufficiency (4), implying an important role of adipose tissue in retinol storage and mobilization.…”

Section: Role Of Rbp4 and Ttr In Vitamin A Metabolismmentioning

confidence: 99%

“…In general, with the increase in the blood glucose concentrations following a meal, the insulin levels increase to enhance the clearance of glucose by inducing the translocation of glut-4 (an insulin-responsive glucose transporter) to plasma membrane in muscle and adipose tissue (5,(7)(8)(9). Therefore, reduced glut-4 level in adipose or muscle is considered as a hallmark of insulin resistance (5,(7)(8)(9).…”

Section: Rbp4 and Its Link To Diabetesmentioning

confidence: 99%

“…Therefore, reduced glut-4 level in adipose or muscle is considered as a hallmark of insulin resistance (5,(7)(8)(9). Interestingly, mice with adipose-selective ablation of glut-4 had normal growth and adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes (8).…”

Section: Rbp4 and Its Link To Diabetesmentioning

confidence: 99%

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Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: The significance of transthyretin

et al. 2012

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SummaryRetinol-binding protein 4 (RBP4) is the principle carrier of retinol in the human plasma, which circulates as a complex with transthyretin (TTR), a homotetrameric thyroxine transport protein. Although this complex formation is thought to prevent glomerular filtration of RBP4, it also stabilizes the quaternary structure of TTR. Recent studies indicate elevated plasma levels of RBP4 in type 2 diabetes (T2D). In contrast, reduced RBP4 levels were observed in type 1 diabetes (T1D). Herein, we critically examine the probable mechanisms involved in the regulation of RBP4 and TTR levels during T2D and T1D. The available evidences point to the involvement of pancreatic factors in regulating the expression of both RBP4 and TTR. It appears that during T1D, TTR levels are reduced and it exists predominantly as a monomer that may interfere its interaction with RBP4 resulting in its loss through glomerular filtration. However, plasma TTR levels remain high under T2D conditions and thus reducing glomerular filtration of RBP4. Therefore, the plasma TTR levels appear to be an important determinant of plasma RBP4 levels in these two diabetic conditions. 2012 IUBMB IUBMB Life, 64(12): 975-982, 2012

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Roles of Gastrointestinal and Adipose Tissue Peptides in Childhood Obesity and Changes After Weight Loss Due to Lifestyle Intervention

Roth

Reinehr

2010

Arch Pediatr Adolesc Med

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hildhood obesity is a global epidemic and associated with an increased risk of hypertension, diabetes mellitus, and coronary heart disease, in addition to psychological disorders. Interventions such as bariatric surgery are highly invasive and lifestyle modifications are often unsuccessful because of disturbed perceptions of satiety. New signaling peptides discovered in recent years that are produced in peripheral tissues such as the gut, adipose tissue, and pancreas communicate with brain centers of energy homeostasis, such as the hypothalamus and hindbrain. This review discusses the major known gut-and adipose tissuederived hormones involved in the regulation of food intake and energy homeostasis and their serum levels in childhood obesity before and after weight loss as well as their relationship to consequences of obesity. Since most of the changes of gastrointestinal hormones and adipokines normalize in weight loss, pharmacological interventions based on these hormones will likely not solve the obesity epidemic in childhood. However, a better understanding of the pathways of body weightand food intake-regulating gut-and adipose tissue-derived hormones will help to find new strategies to treat obesity and its consequences.

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Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

Cited by 1,860 publications

References 45 publications

Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice†

Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice†

Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: The significance of transthyretin

Roles of Gastrointestinal and Adipose Tissue Peptides in Childhood Obesity and Changes After Weight Loss Due to Lifestyle Intervention

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