Molecular Mechanism Of Peripheral Biological Clock And Energy Metabolism Regulating Network Based On PGC - 1α

With the rising and setting of the sun, mammalian circadian system finely controls multiple physiological events, such as sleep/wake cycle, blood pressure, circulating hormones as well as the energy metabolism, which exhibit diurnal fluctuation. Mammalian clock is composed of the central clock located in the hypothalamic suprachiasmatic nucleus (SCN) and the peripheral clock distributed in various tissues. The central clock integrates photic/nonphotic signals to produce rhythmic outputs, then drives the slave oscillators through neuroendocine and behavioral signals. Under normal conditions, these two clocks are tightly coupled, which optimize the energy cycle with the circadian clock, to help body adapt to the cyclic changes of light and food.Recent studies indicate that neuroendocrine and metabolic systems are accurately governed by circadian clock. Approximately 43% genes display circadian rhythm in response to light/dark cycles, many of them encode key metabolic transcriptional cofactors/factors and enzymes, leading to the circadian oscillations of the metabolic processes, such as hepatic gluconeogenesis and bile acid synthesis. More importantly, key clock genes, such as Bmall and RORa, are also crucial factors in the regulation of energy metabolism. In contrast, changes in the nutrient signals (e.g. high fat diet (HFD)) can reset the peripheral clock, resulting in its uncoupling from central pacemaker. Such an uncoupling finally causes the development of metabolic diseases. Collectively, the integration of circadian clock and energy metabolism plays an essential role in maintaining microenvironment homeostasis. Until now, the underling molecular mechanism for the coordinated integration has been extensively studied. There are two well-known integration modes:a. Nuclear receptors, metabolites, and transcriptional cofactors/factors serve as the nodes and simultaneously regulate clock and metabolic processes, thus promote their integration. This integration mode is recognized as the "parallel type"; b. As downstream effectors, clock-controlled genes (CCGs) respond to the clock signals and in turn regulate metabolic processes, thus integrate these two pathways in a "series type" manner.Notably, peroxisome proliferator activated receptor y coactivator lα (PGC-lα), one of the most important regulators in the energy metabolism, integrates hepatic circadian clock and energy metabolism in a "parallel type" way. On the other hand, PGC-la is also sensitive to environmental changes and nutrient signals. It functions as a versatile molecule by binding with various transcriptional factors, like PPARa/p/y/8, ERRα/β/γ, HNF4a, to regulate multiple metabolic processes, such as mitochrondrial biogenesis, brown fat thermogenesis and fasting-induced hepatic gluconeogenesis. However, due to its upstream functions in regulating metabolism, manipulation of PGC-la for the therapy of metabolic diseases will bring non-specific side-effects. Therefore, it is of particular importance to identify PGC-la’s chaperones and downstream effectors, and illustrate their tissue specific clock and metabolic functions. By taking the advantage of this strategy, a more efficient regulation can be obtained.To achieve this goal, we carried out the present study and tried to build up the PGC-1α-oriented transcriptional network. As good examples, one of PGC-1α’s chaperones - Smarcdl, and its downstream effector - Vanin-1 (VNN1), were screened out. We also investigated the role of Smarcdl in the regulation of circadian clock and physiological homeostasis in VSMCs. Furthermore, we illustrated the functions of VNN1, a clock-controlled gene, in mediating PGC-lα-orchestrated hepatic gluconeogenesis.Our results indicated that HFD feeding/FFAs impaired the rhythmicity of Smarcdl and key clock genes in the rat VSMCs. At the molecular level, Smarcdl bound with RORa and synergistically activated the transcriptional activity of bmall promoter. Indeed, the PGC-la mediated the interaction between Smarcdl and RORa. Pathophysiologically, Smarcdl inhibited VSMC proliferation and migration through blocking cell cycle re-entry and the activation of kinase signaling pathways. Collectively, our results demonstrated that Smarcdl is a critical node integrating the circadian clock and VSMC physiological homeostasis.On the other hand, we also found that hepatic VNN1 was rhythmically expressed during a day. It was also induced in the liver of fasted mice or mice with insulin resistance. Liver-specific overexpression of VNN1 disrupted Insulin/Akt pathway, which activated gluconeogenic gene expression and hepatic glucose production, resulting in hyperglycemia. At the molecular level, vnnl transcription was activated by the synergistic interaction of PGC-la and HNF4a. In addition, ChIP analysis indicated that PGC-la was present near HNF4a binding site on the proximal vnnl promoter and turned the chromatin structure into an active state. Taken together, our results illustrated the functions of VNN1, a clock-controlled gene, in mediating PGC-1α-orchestrated hepatic gluconeogenesis.In summary, our results demonstrated that Smarcdl integrated VSMC circadian clock and physiology in a "parallel" way. In contrast, VNN1 responded to the clock signals and in turn regulated hepatic gluconeogenesis, thus integrated the circadian clock and hepatic glucose metabolism in a "series type" manner. These results extend the current understandings to the integration between circadian clock and energy metabolism. Meanwhile, these data also provide two promising molecular targets for the therapy of metabolic diseases through the view of chronobiology.