PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and GL expression

Abstract

The interplay between hepatic glycogen metabolism and blood glucose levels is a paradigm of the rhythmic nature of metabolic homeostasis. Here we show that mice lacking a functional PER2 protein (Per2 (Brdm1) ) display reduced fasting glycemia, altered rhythms of hepatic glycogen accumulation, and altered rhythms of food intake. Per2 (Brdm1) mice show reduced hepatic glycogen content and altered circadian expression during controlled fasting and refeeding. Livers from Per2 (Brdm1) mice display reduced glycogen synthase protein levels during refeeding, and increased glycogen phosphorylase activity during fasting. The latter is explained by PER2 action on the expression of the adapter proteins PTG and GL, which target the protein phosphatase-1 to glycogen to decrease glycogen phosphorylase activity. Finally, PER2 interacts with genomic regions of Gys2, PTG, and G L . These results indicate an important role for PER2 in the hepatic transcriptional response to feeding and acute fasting that promotes glucose storage to liver glycogen.

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…In fact, compared with mice with global Bmal1 deletion, liver-specific Bmal1 knockout mice have relative hypoglycaemia, in line with impaired gluconeogenesis [72]. Similarly, Per2 Brdm1 mutant mice (lacking a functional PER2 protein) display reduced glucose levels compared with wild-type mice during periods of fasting, indicating that PER2 can also influence glucose synthesis [10,75]. PER2 is known to interact with PPARα and REV-ERBα, both of which regulate the expression of the gluconeogenic enzyme, glucose-6-phosphatase (G6Pase) [11].…”

“…PER2 is known to interact with PPARα and REV-ERBα, both of which regulate the expression of the gluconeogenic enzyme, glucose-6-phosphatase (G6Pase) [11]. Daily rhythms of the glucose transporter, GLUT2, in the liver are also eliminated in both Bmal1 −/− and Per2 Brdm1 mutant mice [72,75].…”

Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

“…The liver is considered a peripheral clock, in the sense that it can regulate various metabolic pathways depending on the expression of certain molecular clocks such as the PER and CRY family proteins (Sahar & Sassone-Corsi 2012). There is growing evidence of the reverse process, by which the metabolic state regulates PER2, which in turn controls hepatic glycogen storage/ degradation (Tahara et al 2011, Zani et al 2013. Supporting previous findings, per2 regulation may limit glucose production by increasing glycogen storage or preventing glycogenolysis in obese zebrafish.…”

Immunometabolism: Is it under the eye of the clock?

“…Il-6 and Tnf˛ RNA. Lower NF-B activation [147] Cry1 (AP-Tg) Global • Elevated glucose levels in serum and urine [161] • Common symptoms of diabetes mellitus, polydipsia and polyuria [161] Per2 Global • Reduced levels of triacylglycerol and non-sterified fatty acids [139] • Enhanced adipocyte differentiation [139] • Increased plasma insulin and impaired gluconeogenesis [142,143] • Protected from sepsis-induced death [144] • Lower IL-1␤ and IFNϒ in serum [144] • Lower Tlr9 expression [82] Per3 Global • Enhanced adipogenesis [139] • Increased adipose tissue and decreased muscle tissue mass [139] Rev-erb˛ Global • Increased adiposity and mild hyperglycemia [119] • Altered lipid and glucose metabolism [119] • Increase in G6Pase and PEPCK [120] • Increased IL-6 in serum [124] ROR˛ sg/sg Global • Reduced adiposity and protection from obesity [128] • Lower serum and liver triglyceride levels [128] • Impaired Th17 cell development [133] • Highly susceptible to LPS induced sepsis [136] ROR Global • Enhanced production of insulin sensitive adipocytes.…”

“…Global Per3 knock out mice exhibit increased deposits of adipose tissue and reduced muscle tissue in comparison to wild-type mice [140]. PER proteins have also been linked to glucose storage with Per2-/-mice exhibiting a loss of rhythmic glycogen accumulation in the liver, impaired gluconeogenesis and elevated plasma insulin levels [141][142][143].…”