Peroxisome Proliferator-Activated Receptors-α and -γ, and cAMP-Mediated Pathways, Control Retinol-Binding Protein-4 Gene Expression in Brown Adipose Tissue

• Published in: Endocrinology (Philadelphia) Vol. 153; no. 3; pp. 1162 - 1173
• Main Authors: Rosell, Meritxell, Hondares, Elayne, Iwamoto, Sadahiko, Gonzalez, Frank J., Wabitsch, Martin, Staels, Bart, Olmos, Yolanda, Monsalve, Maria, Giralt, Marta, Iglesias, Roser, Villarroya, Francesc
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Oxford University Press 01.03.2012; Endocrine Society
• Subjects: Adipocytes; Adipose tissue; Adipose tissue (brown); Adipose Tissue - metabolism; Adipose Tissue, Brown - metabolism; Animals; Biological and medical sciences; Body fat; Cyclic AMP; Cyclic AMP - metabolism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Gene regulation; Insulin Resistance; Low temperature resistance; Mice; Models, Biological; Norepinephrine; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Peroxisome proliferator-activated receptors; PPAR alpha - antagonists & inhibitors; PPAR alpha - metabolism; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; Promoter Regions, Genetic; Protein biosynthesis; Protein synthesis; Protein transport; Proteins; Receptors; Regulatory sequences; Retinol-binding protein; Retinol-Binding Proteins, Plasma - biosynthesis; Serum proteins; Signal transduction; Thiazolidinediones - pharmacology; Trans-Activators - metabolism; Transcription Factors - metabolism; Up-Regulation; Vertebrates: endocrinology; Vitamin A; Micronutrient; Binding protein; PPAR-α receptor; Vitamin; Cyclic AMP; Brown adipose tissue; Gene expression; Retinol
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2011-1367

Retinol binding protein-4 (RBP4) is a serum protein involved in the transport of vitamin A. It is known to be produced by the liver and white adipose tissue. RBP4 release by white fat has been proposed to induce insulin resistance. We analyzed the regulation and production of RBP4 in brown adipose tissue. RBP4 gene expression is induced in brown fat from mice exposed to cold or treated with peroxisome proliferator-activated receptor (PPAR) agonists. In brown adipocytes in culture, norepinephrine, cAMP, and activators of PPARγ and PPARα induced RBP4 gene expression and RBP4 protein release. The induction of RBP4 gene expression by norepinephrine required intact PPAR-dependent pathways, as evidenced by impaired response of the RBP4 gene expression to norepinephrine in PPARα-null brown adipocytes or in the presence of inhibitors of PPARγ and PPARα. PPARγ and norepinephrine can also induce the RBP4 gene in white adipocytes, and overexpression of PPARα confers regulation by this PPAR subtype to white adipocytes. The RBP4 gene promoter transcription is activated by cAMP, PPARα, and PPARγ. This is mediated by a PPAR-responsive element capable of binding PPARα and PPARγ and required also for activation by cAMP. The induction of the RBP4 gene expression by norepinephrine in brown adipocytes is protein synthesis dependent and requires PPARγ-coactivator-1-α, which acts as a norepinephine-induced coactivator of PPAR on the RBP4 gene. We conclude that PPARγ- and PPARα-mediated signaling controls RBP4 gene expression and releases in brown adipose tissue, and thermogenic activation induces RBP4 gene expression in brown fat through mechanisms involving PPARγ-coactivator-1-α coactivation of PPAR signaling.