Night-time restricted feeding normalises clock genes and Pai-1 gene expression in the db/db mouse liver

Abstract

Aims/hypothesis. An increase in PAI-1 activity is thought to be a key factor underlying myocardial infarction. Mouse Pai-1 (mPai-1) activity shows a daily rhythm in vivo, and its transcription seems to be controlled not only by clock genes but also by humoral factors such as insulin and triglycerides. Thus, we investigated daily clock genes and mPai-1 mRNA expression in the liver of db/db mice exhibiting high levels of glucose, insulin and triglycerides. Methods. Locomotor activity was measured using an infrared detection system. RT-PCR or in situ hybridisation methods were applied to measure gene expression. Humoral factors were measured using measurement kits. Results. The db/db mice showed attenuated locomotor activity rhythms. The rhythmic expression of mPer2 mRNA was severely diminished and the phase of mBmal1 oscillation was advanced in the db/db mouse liver, whereas mPai-1 mRNA was highly and constitutively expressed. Night-time restricted feeding led to a recovery not only from the diminished locomotor activity, but also from the diminished Per2 and advanced mBmal1 mRNA rhythms. Expression of mPai-1 mRNA in db/db mice was reduced to levels far below normal. Pioglitazone treatment slightly normalised glucose and insulin levels, with a slight reduction in mPai-1 gene expression. Conclusions/interpretation. We demonstrated that Type 2 diabetes impairs the oscillation of the peripheral oscillator. Night-time restricted feeding rather than pioglitazone injection led to a recovery from the diminished locomotor activity, and altered oscillation of the peripheral clock and mPai-1 mRNA rhythm. Thus, we conclude that scheduled restricted food intake may be a useful form of treatment for diabetes.

The hepatic circadian clock is preserved in a lipid-induced mouse model of non-alcoholic steatohepatitis

“…Kohsaka et al [13] reported that a high-fat diet lengthened the period of locomotor activity rhythm under constant darkness in mice, but the effect was not detected under a 12-h light/12-h dark cycle. Moreover, night-time restricted feeding can normalize the impaired circadian clock in the livers of db/db mice [34]. These results suggest Consistent with the intact intracellular clock, the daily expression rhythms of most circadianly expressed genes examined were preserved in the livers of mice with NASH.…”

Chronic mild stress alters circadian expressions of molecular clock genes in the liver

“…At 9 wk of age, they were divided into two groups, one continuously housed as stated above (control) and the other subjected to 1 wk of unpredictable CMS. At 10 wk of age, 24 mice of each strain were killed by cervical dislocation at 6-h intervals over 24 h (2,4,28,46) to obtain liver and brain samples at zeitgeber times (ZTs) 3, 9, 15, and 21 in which ZT 0 is defined as lights on and ZT 12 as lights off (n ϭ 6/group for each observation point). All animal studies were conducted in accordance with the institutional guidelines for animal experiments and were approved by Tohoku University.…”

“…Genetically obese strains such as KK-Ay (3) and db/db mice (28), and mice with high-fat diet-induced obesity (27), exhibit attenuated circadian expressions of several clock genes in the liver. Intriguingly, in all of these murine models, serum corticosterone levels were shown to be altered (1,27).…”

Sleep and circadian rhythms: Key components in the regulation of energy metabolism

“…For example, sleep deprivation has been shown to shift the circadian clock, even when stress and overall activity levels have been controlled [49]. In murine models of obesity and diabetes, it is common to find attenuated rhythms of food intake, locomotor activity, and body temperature [50][51][52][53]. Intriguingly, when db/db mice, Zucker obese rats, and H1 receptor deficient mice are provided with food only during the dark phase, their increase in weight gain is attenuated, locomotor rhythms are improved, and other altered metabolic parameters show improvement [50][51][52].…”

“…In murine models of obesity and diabetes, it is common to find attenuated rhythms of food intake, locomotor activity, and body temperature [50][51][52][53]. Intriguingly, when db/db mice, Zucker obese rats, and H1 receptor deficient mice are provided with food only during the dark phase, their increase in weight gain is attenuated, locomotor rhythms are improved, and other altered metabolic parameters show improvement [50][51][52]. The ability of a high fat diet to induce weight gain is prevented when rats are fed only during the primary eating phase, the dark period [54].…”