These results reveal an important, but previously unexplored, role of SMC BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1, which may mediate the AAA protective effect of SMC BMAL1 deletion.

In murine models of obesity/diabetes there is an increase in plasma SAA levels along with redistribution of SAA from high density lipoprotein (HDL) to apo-B containing lipoprotein particles, namely low density lipoprotein (LDL) and very low density lipoprotein (VLDL). The goal of this study was to determine if obesity is associated with similar SAA lipoprotein redistribution in humans. Three groups of obese individuals were recruited from a weight loss clinic: healthy obese (n=14), metabolic syndrome obese (n=8) and obese with type 2 diabetes (n=6). Plasma was separated into lipoprotein fractions by fast protein liquid chromatography (FPLC) and SAA was measured in lipid fractions using enzyme-linked immunosorbent assay (ELISA) and western blotting. Only the obese diabetic group had SAA detectable in apoB-containing lipoproteins, and SAA reverted back to HDL with active weight loss. In human subjects, SAA is found in apo-B containing lipoprotein particles only in obese subjects with type 2 diabetes, but not healthy obese, or obese subjects with metabolic syndrome.

The quantity and quality of food intake have been considered crucial for peoples' wellness. Only recently has it become appreciated that the timing of food intake is also critical. Nondipping blood pressure (BP) is prevalent in diabetic patients and is associated with increased cardiovascular events. However, the causes and mechanisms of nondipping BP in diabetes are not fully understood. Here, we report that food intake and BP were arrhythmic in diabetic db/db mice fed a normal chow diet ad libitum. Imposing a food intake diurnal rhythm by time-restricted feeding (TRF; food was only available for 8 h during the active phase) prevented db/db mice from developing nondipping BP and effectively restored the already disrupted BP circadian rhythm in db/db mice. Interestingly, increasing the time of food availability from 8 h to 12 h during the active dark phase in db/db mice prompted isocaloric feeding and still provided robust protection of the BP circadian rhythm in db/db mice. In contrast, neither 8-h nor 12-h TRF affected BP dipping in wild-type mice. Mechanistically, we demonstrate that TRF protects the BP circadian rhythm in db/db mice via suppressing the sympathetic activity during the light phase when they are inactive and fasting. Collectively, these data reveal a potentially pivotal role of the timing of food intake in the prevention and treatment of nondipping BP in diabetes.

Diabetic patients have an increased prevalence of blood pressure (BP) circadian rhythm disruption, which is associated with increased risk of target organ damage and detrimental cardiovascular events. Limited information is available regarding the role of clock genes in the disruption of the BP circadian rhythm in diabetes due to the lack of a diabetic animal model that allows real-time monitoring of clock gene oscillation. Here, we generated a novel diabetic db/db-mPer2 Luc mouse model by crossing the type 2 diabetic db/db mice with the mPer2 Luc knock-in mice. The daily rhythms of BP, heart rate, locomotor activity, and food and water intake were acquired by radiotelemetry or metabolic chambers. The daily oscillation of mPer2 bioluminescence was recorded by LumiCycle in real-time in tissue explants and by IVIS system in vivo. Our results showed that the db/db-mPer2 Luc mice were obese, diabetic and glucose intolerant. The db/db-mPer2 Luc mice displayed a compromised BP daily rhythm, which was associated with the disruption of the daily rhythms in baroreflex sensitivity, locomotor activity, and metabolism, but not heart rate or food and water intake. The phase of the mPer2 daily oscillation was advanced to different extents in the explanted peripheral tissues from the db/db-mPer2 Luc mice relative to that in the control mice. In contrast, no phase shift was detected in the mPer2 daily oscillation in the explanted suprachiasmatic nucleus (SCN). Moreover, the advanced phase shift of the mPer2 daily oscillation was also detected in the liver, kidney and submandibular gland in vivo in the db/db-mPer2 Luc mice. In conclusion, the diabetic db/db-mPer2 Luc mouse is a novel animal model that allows real-time monitoring of mPer2 circadian rhythms ex vivo and in vivo. The results from db/db-mPer2 Luc mice suggest that the desynchrony of mPer2 daily oscillation in the peripheral tissues contributes to the loss of BP daily oscillation in diabetes.

People with diabetes are more likely to experience sleep disturbance than those without. Sleep disturbance can cause daytime sleepiness in diabetic patients, which may impair their daytime performance or even lead to workplace injuries. Therefore, restoring the normal sleep-wake cycle is critical for diabetic patients who experience daytime sleepiness. Previous data on a diabetic mouse model, the db/db mice, have demonstrated that the total sleep time and sleep fragmentation are increased and the daily rhythm of the sleep-wake cycle is attenuated. Accumulating evidence has shown that active time-restricted feeding (ATRF), in which the timing of food availability is restricted to the active-phase, is beneficial to metabolic health. However, it is unknown whether ATRF restores the normal sleep-wake cycle in diabetes. To test that, we used a non-invasive piezoelectric system to monitor the sleep-wake profile in the db/db mice with ad libitum feeding (ALF) as a baseline and then followed with ATRF. The results showed that at baseline, db/db mice exhibited abnormal sleep-wake patterns: the sleep time percent during the light-phase was decreased, while during the dark-phase it was increased with unusual cycling compared to control mice. In addition, the sleep bout length during both the light-phase and the full 24-h period was shortened in db/db mice. Analysis of the sleep-wake circadian rhythm showed that ATRF effectively restored the circadian but suppressed the ultradian oscillations of the sleep-wake cycle in the db/db mice. In conclusion, ATRF may serve as a novel strategy for treating diabetes-induced irregularity of the sleep-wake cycle.