Jiao-tai-wan Up-regulates Hypothalamic and Peripheral Circadian Clock Gene Cryptochrome and Activates PI3K/AKT Signaling in Partially Sleep-deprived Rats

摘要

This study aims to explore the effect and mechanism of Jiao-tai-wan (JTW) on systemic and tissue-specific inflammation and insulin resistance in obesity-resistant (OR)rats with chronic partial sleep deprivation (PSD).OR rats with PSD were orally given JTW and Estazolam for 4 weeks.The amount of food intake and metabolic parameters such as body weight increase rate,fasting plasma glucose (FPG),fasting insulin (FINS),homeostasis model assessment-insulin resistance (HOMA-IR) and plasma inflammatory markers were measured.The expression levels of circadian proteins cryptochrome 1 (Cry1)and cryptochrome 2 (Cry2) in hypothalamus,adipose and liver tissues were also determined.Meanwhile,the mRNA expression of inflammatory markers,activity of nuclear factor kappa B (NF-κB) p65 protein,as well as the expression levels of insulin signaling pathway proteins in hypothalamus,adipose and liver tissues were measured.Additionally,cyclic adenosine 3',5'-monophosphate (cAMP) and activity of vasodilator-stimulated phosphoprotein (VASP)in hypothalamus tissue were measured.JTW significantly decreased the body weight increase rate and food intake,ameliorated systemic inflammation and insulin resistance.JTW effectively ameliorated inflammation and increased PI3K/AKT signaling activation in hypothalamus,adipose and liver.Interestingly,all these changes were associated with the up-regulation of circadian gene Cryl and Cry2 protein expression.We also found that in hypothalamus tissue of P SD rats,down-regulation of Cry 1 and Cry2 activated cAMP/PKA signaling and then led to inflammation,while JTW inhibited this signaling.These results suggested that JTW has the beneficial effect on ameliorating inflammation and insulin resistance in partially sleep-deprived rats by up-regulating Cry expression.