It has long been appreciated that insulin action is closely tied to circadian rhythms. However, mechanisms that dictate diurnal insulin sensitivity in metabolic tissues are not well understood. Retinol binding protein 4 (RBP4) has been implicated as a driver of insulin resistance in rodents and humans, and has become an attractive drug target in type 2 diabetes. RBP4 is synthesized primarily in the liver where it binds retinol and transports it to tissues throughout the body. The retinol-RBP4 complex (holo-RBP) can be recognized by a cell surface receptor known as stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. Coupled to retinol transport, holo-RBP can activate STRA6-driven janus kinase (JAK) signaling and downstream induction of signal transducer and activator of transcription (STAT) target genes. Here we examined diurnal rhythmicity of the RBP4-STRA6 signaling axis, and investigated whether STRA6 is necessary for diurnal variations in insulin sensitivity. We show that adipose tissue STRA6 undergoes circadian patterning driven in part by the nuclear transcription factor Rev-erbα. Furthermore, STRA6 is necessary for diurnal rhythmicity of insulin action and JAK/STAT signaling in adipose tissue. These findings establish that holo-RBP and its receptor STRA6 are potent regulators of diurnal insulin responses, and suggest that the holo-RBP/STRA6 signaling axis may represent a novel therapeutic target in type 2 diabetes.

作者：Christy M, Gliniak；J Mark, Brown；Noa, Noy

来源：The Journal of biological chemistry 2017 年