Retinol-Binding Protein 4 and Its Membrane Receptor STRA6 Control Adipogenesis by Regulating Cellular Retinoid Homeostasis and Retinoic Acid Receptor α Activity

Muenzner, Matthias; Tuvia, Neta; Deutschmann, Claudia; Witte, Nicole; Tolkachov, Alexander; Valai, Atijeh; Henze, Andrea; Sander, Leif Erik; Raila, Jens; Schupp, Michael

doi:10.1128/mcb.00221-13

Cited by 78 publications

(76 citation statements)

References 79 publications

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“…7F). One cause for this could be decreased adipocyte differentiation since knockdown of STRA6 in cultured adipocytes was recently shown to impair adipocyte differentiation in the presence of holo-RBP4 (30). However, we did not find differences in white adipocyte differentiation markers, indicating that the reduced adipocyte number did not result from impaired differentiation.…”

Section: Discussioncontrasting

confidence: 43%

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Zemany

Kraus

Norseen

et al. 2014

Molecular and Cellular Biology

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bTo investigate the mechanisms by which elevated retinol-binding protein 4 (RBP4) causes insulin resistance, we studied the role of the high-affinity receptor for RBP4, STRA6 (stimulated by retinoic acid), in insulin resistance and obesity. In high-fat-diet-fed and ob/ob mice, STRA6 expression was decreased 70 to 95% in perigonadal adipocytes and both perigonadal and subcutaneous adipose stromovascular cells. To determine whether downregulation of STRA6 in adipocytes contributes to insulin resistance, we generated adipose-Stra6 ؊/؊ mice. Adipose-Stra6 ؊/؊ mice fed chow had decreased body weight, fat mass, leptin levels, insulin levels, and adipocyte number and increased expression of brown fat-selective markers in white adipose tissue. When fed a highfat diet, these mice had a mild improvement in insulin sensitivity at an age when adiposity was unchanged. STRA6 has been implicated in retinol uptake, but retinol uptake and the expression of retinoid homeostatic genes (encoding retinoic acid receptor ␤ [RAR␤], CYP26A1, and lecithin retinol acyltransferase) were not altered in adipocytes from adipose-Stra6 ؊/؊ mice, indicating that retinoid homeostasis was maintained with STRA6 knockdown. Thus, STRA6 reduction in adipocytes in adipose-Stra6 ؊/؊ mice fed chow resulted in leanness, which may contribute to their increased insulin sensitivity. However, in wild-type mice with high-fat-diet-induced obesity and in ob/ob mice, the marked downregulation of STRA6 in adipocytes and adipose stromovascular cells does not compensate for obesity-associated insulin resistance.T hree hundred fifty million people worldwide have diabetes (1), and the impact will be staggering if we do not develop more effective methods for early detection and treatment. Serum retinol-binding protein 4 (RBP4) is elevated in humans and rodents with insulin resistance and type 2 diabetes (2-4), and data suggest that it may play a causative role (4, 5). Injection of purified RBP4 or overexpression of RBP4 in mice causes insulin resistance (4). Furthermore, a gain-of-function polymorphism in the RBP4 promoter is associated with an 80% increased risk of developing diabetes in humans (5). In addition, epidemiologic studies in several ethnic backgrounds indicate that elevated RBP4 is an early marker of prediabetes (6) and metabolic syndrome (7,8) and is associated with a 3.6-fold increased risk of myocardial infarction (9).The mechanisms by which RBP4 causes insulin resistance and whether the actions of RBP4 depend on a receptor are questions of high interest in the field. STRA6 is a high-affinity cell surface receptor for RBP4 that mediates vitamin A uptake (10). STRA6 is highly expressed in blood-organ barriers and in the brain, eye, kidney, testis, and female reproductive tract, and it is absent from the liver (11). STRA6 is upregulated in some tumors, and its expression can be induced by retinoids and increased Wnt-1 expression in mammary epithelial cells (12). RBP4 mediates insulin resistance through STRA6-independent (13, 14) and STRA6-dependent pathwa...

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Section: Discussioncontrasting

confidence: 43%

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Zemany

Kraus

Norseen

et al. 2014

Molecular and Cellular Biology

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“…In adipocyte precursor cells, Stra6 mediates bidirectional retinol transport, depending on whether RBP4 is retinol-bound (19).…”

mentioning

confidence: 99%

An Alternative Retinoic Acid-responsive Stra6 Promoter Regulated in Response to Retinol Deficiency

Laursen¹,

Kashyap²,

Scandura

et al. 2015

Journal of Biological Chemistry

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“…RBP4 is a protein that binds retinol and transports it in the circulation [15]. It also coordinates retinol uptake by adipose tissues and, through this function, retinol-dependent adipogenesis [38]. RBP4, which is produced mainly by the liver, is also expressed in adipose tissue, and this expression is markedly higher in VF than SF [26].…”

Section: Discussionmentioning

confidence: 99%

Dietary Vitamin A and Visceral Adiposity: A Modulating Role of the Retinol-Binding Protein 4 Gene

Goodwin

Abrahamowicz²,

Leonard

et al. 2015

Lifestyle Genomics

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Background/Aims: Visceral fat (VF) compared with subcutaneous fat (SF) is more closely associated with cardiometabolic disease. Dietary vitamin A (retinol) may reduce adiposity through its effects on adipogenesis differentially in VF and SF, and this effect may be modulated by retinol-binding protein-4 (RBP4). We investigated whether intake of vitamin A is associated with either VF or SF, and whether this association is moderated by the RBP4 genotype (rs10882272, C/T) previously associated with circulating retinol levels. Methods: This was a cross-sectional association study in a sample of 947 adolescents from a French-Canadian founder population. VF and SF were quantified with magnetic resonance imaging, and vitamin A intake was assessed with a 24-hour food recall. All participants were genotyped to determine their RBP4 variant. Results: Dietary intake of vitamin A was negatively associated with VF; however, it was not associated with SF. These relationships were independent of age, sex, height and energy intake, and were modulated by the RBP4 variant. The T allele promoted adiposity-reducing effects of vitamin A in VF and adiposity-enhancing effects in SF, while the C allele had adiposity-reducing effects in both VF and SF. Conclusions: Dietary vitamin A may reduce abdominal adiposity and promote visceral to subcutaneous body fat redistribution during adolescence in an RBP4-dependent manner. These observational findings provide the basis for future interventional studies, which together with genetic information may inject further causality in the association between dietary vitamin A intake and abdominal adiposity.

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Retinol-Binding Protein 4 and Its Membrane Receptor STRA6 Control Adipogenesis by Regulating Cellular Retinoid Homeostasis and Retinoic Acid Receptor α Activity

Cited by 78 publications

References 79 publications

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

An Alternative Retinoic Acid-responsive Stra6 Promoter Regulated in Response to Retinol Deficiency

Dietary Vitamin A and Visceral Adiposity: A Modulating Role of the Retinol-Binding Protein 4 Gene

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