Period2 gene mutant mice show compromised insulin-mediated endothelial nitric oxide release and altered glucose homeostasis

Abstract

Period2 (Per2) is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial nitric oxide (NO) production in response to insulin in the mPer2Brdm1 mice. We show that mPer2Brdm1 mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated NO release in the aortas in both active and inactive phases of the animals. As compared to wild type (WT) mice, the mPer2Brdm1 mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2Brdm1 mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to WT controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin-stimulated NO release, independently of obesity.

Physical activity, and not fat mass is a primary predictor of circadian parameters in young men

“…Similar to previous reports, we demonstrated significantly lower temperature amplitude and stability in our obese group of subjects (Corbalán-Tutau et al, 2011). We also concurred with previous findings (Atkinson et al, 2007; Carvas et al, 2012; Colwell & Matveyenko, 2014; Garaulet & Gomez-Abellan, 2014) that several physiological and behavioral measures were significantly associated with circadian rhythm parameters when the total group, and adiposity groups were examined separately. It was interesting to note that we detected changes in circadian amplitude and stability parameters in subjects with only one MetS risk factor compared to those with no MetS factors.…”

“…This may result in a desynchronization or misalignment of the central and peripheral clocks with associated disruption in organ and system circadian rhythms. Studies have demonstrated that forced desynchrony in humans and rodents is associated with significant adverse changes in risk factors for cardiometabolic disease (Barclay et al, 2012; Carvas et al, 2012; Froy, 2010; Garaulet & Madrid, 2009; Marcheva et al, 2010; Muller et al, 1985). …”

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“…In addition, their glucose and lipid metabolism is disturbed, resulting in hyperglycemia, hypoinsulinemia, and hyperlipidemia. Like the Clock-d19 mice, Per2 Brdm1-/-mice also show a mania-like behavior, arrhythmic food intake, hyperphagia, and, at least in the first four months of their life, increased body weight [72][73][74][75]. However, unlike Clock-d19 mice, they These studies show that genetic perturbations of circadian rhythms simultaneously alter both mood regulation and central metabolic functions.…”

Relevance of Circadian Rhythm in Cancer

“…Similarly, Per2 mutant mice have lower body fat content and total body weight, and show aberrations in blood glucose regulation, with fasting hypoglycemia, impaired gluconeogenesis and increased insulin sensitivity despite being hyperinsulinemic [102]. Rev-erbα -/-animals have increased white adipose tissue, elevated blood glucose, decreased blood lipid levels, and abnormal bile acid levels [103,104].…”