title: Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor α activity.
abstract: Retinoids are vitamin A (retinol) derivatives and complex regulators of adipogenesis by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Circulating retinol-binding protein 4 (RBP4) and its membrane receptor STRA6 coordinate cellular retinol uptake. It is unknown whether retinol levels and the activity of RAR and RXR in adipocyte precursors are linked via RBP4/STRA6. Here, we show that STRA6 is expressed in precursor cells and, dictated by the apo- and holo-RBP4 isoforms, mediates bidirectional retinol transport that controls RARα activity and subsequent adipocyte differentiation. Mobilization of retinoid stores in mice by inducing RBP4 secretion from the liver activated RARα signaling in the precursor cell containing the stromal-vascular fraction of adipose tissue. Retinol-loaded holo-RBP4 blocked adipocyte differentiation of cultured precursors by activating RARα. Remarkably, retinol-free apo-RBP4 triggered retinol efflux that reduced cellular retinoids, RARα activity, and target gene expression and enhanced adipogenesis synergistically with ectopic STRA6. Thus, STRA6 in adipocyte precursor cells links nuclear RARα activity to the circulating RBP4 isoforms, whose ratio in obese mice was shifted toward limiting the adipogenic potential of their precursors. This novel cross talk identifies a retinol-dependent metabolic function of RBP4 that may have important implications for the treatment of obesity.
authors: Department of Endocrinology, Diabetes, and Nutrition and Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany.
authors: Matthias
authors: M
authors: Muenzner
authors: Neta
authors: N
authors: Tuvia
authors: Claudia
authors: C
authors: Deutschmann
authors: Nicole
authors: N
authors: Witte
authors: Alexander
authors: A
authors: Tolkachov
authors: Atijeh
authors: A
authors: Valai
authors: Andrea
authors: A
authors: Henze
authors: Leif E
authors: LE
authors: Sander
authors: Jens
authors: J
authors: Raila
authors: Michael
authors: M
authors: Schupp
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006706:Homeostasis; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014801:Vitamin A / Q000097:blood*
chemical_list: D008565:Membrane Proteins; C000607072:Rara protein, mouse; C502487:Rbp4 protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D054839:Retinol-Binding Proteins, Plasma; C108001:Stra6 protein, mouse; D014801:Vitamin A
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