RBP4 functions as a hepatokine in the regulation of glucose metabolism by the circadian clock in mice.

AIMS/HYPOTHESIS: As one of the key adipokines, retinol binding protein 4 (RBP4) is suggested to positively correlate with insulin resistance; however, not all clinical studies support this association. Although some explanations are proposed for this discrepancy, the temporal aspect of RBP4 secretion has not been considered. Aryl hydrocarbon receptor nuclear translocator-like (also known as BMAL1) and its target D site-binding protein (DBP) are both pivotal transcription factors of the circadian core clock. Given the overwhelming presence of circadian control in metabolism and the principal role of the liver in RBP4 secretion, we hypothesised that RBP4 may oscillate under the control of BMAL1 and act as a hepatokine, participating in the maintenance of glucose homeostasis by the circadian clock.

METHODS: We used liver-specific Bmal1 (also known as Arntl)-knockout mice and recombinant adenoviruses expressing short-hairpin RNA (shRNA) specific for Dbp or Rbp4 in the liver.

RESULTS: RBP4 displayed diurnal oscillations in the liver and plasma, which were dampened in liver-specific-Bmal1-knockout mice. BMAL1 regulated hepatic RBP4 expression via its direct target, DBP. Hepatic knockdown of RBP4 or DBP increased whole-body insulin sensitivity in mice in a time-of-day-dependent manner. Conversely, hepatic overexpression of RBP4 reversed the insulin-sensitising effects of liver-specific depletion of BMAL1.

CONCLUSIONS/INTERPRETATION: Our results not only provide a novel mechanism for circadian regulation of RBP4, but also unveil a critical role of RBP4, acting as a hepatokine in the regulation of glucose metabolism by the circadian clock.