Forced internal desynchrony induces cardiometabolic alterations in adult rats

in Journal of Endocrinology
Correspondence should be addressed to D A Rosa: danielr@ufg.br
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Disruptions in circadian rhythms have been associated with several diseases, including cardiovascular and metabolic disorders. Forced internal desynchronization induced by a period of T-cycles of 22 h (T22 protocol) reaches the lower limit of entrainment and dissociates the circadian rhythmicity of the locomotor activity into two components, driven by different outputs from the suprachiasmatic nucleus (SCN). The main goal of this study was to evaluate the cardiovascular and metabolic response in rats submitted to internal desynchronization by T22 protocol. Male Wistar rats were assigned to either a control group subjected to a usual T-cycles of 24 h (12 h–12 h) or an experimental group subjected to the T22 protocol involving a 22-h symmetric light–dark cycle (11 h–11 h). After 8 weeks, rats subjected to the T22 exhibited desynchrony in their locomotor activity. Although plasma glucose and insulin levels were similar in both groups, desynchronized rats demonstrated dyslipidemia, significant hypertrophy of the fasciculate zone of the adrenal gland, low IRB, IRS2, PI3K, AKT, SOD and CAT protein expression and an increased expression of phosphoenolpyruvate carboxykinase in the liver. Furthermore, though they maintained normal baseline heart rates and mean arterial pressure levels, they also presented reduced baroreflex sensitivity. The findings indicate that circadian timing desynchrony following the T22 protocol can induce cardiometabolic disruptions. Early hepatic metabolism dysfunction can trigger other disorders, though additional studies are needed to clarify the causes.

 

      Society for Endocrinology

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    Graphs of representative spontaneous locomotor activity. (A) Double-plotted actograms of locomotor activity of representative rats maintained on a symmetric T24 h (left; 12 h–12 h light–dark) or T22 h cycle (right; 11 h–11 h light–dark). White arrow indicates the time of euthanasia for sample collection or cardiovascular test. (B) Sokolove–Bushell periodograms correspondent to the time series of each actogram. Analysis revealed a single peak at T24 h (left) for control animals (CTR) and two peaks for animals subjected to the desynchronization protocol (right, DSC); the first peak represents entrainment with the T22 h light–dark cycle, whereas the second one represents the period of free running for more than 24 h (representative rat = 25 h). %V = percentage of variance.

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    Effect of circadian rhythm desynchronization on locomotor activity. (A) Similar cumulative total amount of locomotor activity in rats in the control (CTR, N = 13, white bars) and desynchronized (DSC, N = 19, black bars) groups. (B) Percentage of locomotor activity during normal rest (light phase) and activity (dark phase) periods of the light–dark cycle. Both groups showed more activity during the dark than the light phase; however, DSC rats (black bars) showed higher locomotor activity during the light phase and lower locomotor activity during the dark phase than CTR rats (white bars) group. *P < 0.05 indicates a significant difference with an unpaired Student’s t test or two-way ANOVA following by post hoc Bonferroni’s test. a.u., arbitrary unit.

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    Effect of circadian rhythm desynchronization on adrenal gland morphology. (A) Representative photomicrographs (5× magnification, scale bars = 500 µm and ×100 magnification, scale bars = 25 µm) showing adrenal gland sections stained with hematoxylin–eosin from control (CTR, left) and desynchronized (DSC, right) rats. Adrenal gland mass and total, cortical and zona fasciculata area increased in DSC rats compared to controls (B, C, E and F, respectively). DSC rats showing reduced number of nuclei per µm2 in the zona fasciculata of the adrenal cortex (G). Although adrenal medullary area did not differ between the groups (D). Data are presented as mean ± s.e.m. (n = 6 each group). *P < 0.05 indicates a significant difference from CTR rats according to an unpaired Student’s t test. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0026.

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    Effect of circadian rhythm desynchronization on insulin signaling proteins in rat livers. (A) Western blot analysis revealing fewer IRB (A), IRS2 (B), PI3K (C) and AKT (D) proteins in desynchronized (DSC) rats than in control (CTR) rats. (E) Representative blots of proteins. GAPDH content was used as control loading. Results are expressed as relative (%) to CTR rats and as mean ± s.e.m. (n = 6). *P < 0.05 indicates a significant difference from CTR rats according to an unpaired Student’s t test.

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    Effect of circadian rhythm desynchronization on gluconeogenic enzyme protein in rat livers. (A) Western blot quantitative analysis showing increased PEPCK protein in desynchronized (DSC) rats. (B) Representative blots of proteins. GAPDH content was used as control loading. Results are expressed as relative (%) to the control group and as mean ± s.e.m. (n = 6). *P < 0.05 indicates a significant difference from CTR rats according to an unpaired Student’s t test.

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    Effect of circadian rhythm desynchronization on antioxidant defense proteins in rat livers. (A) Reduced SOD (A) and CAT (B) among desynchronized (DSC) rats. (C) Representative Western blot of SOD and CAT from the control (CTR) and DSC rats. GAPDH content was used as control loading. Results are expressed as relative (%) to CTR rats and as mean ± s.e.m. (n = 6). *P < 0.05 indicates a significant difference from CTR rats according to an unpaired Student’s t test.

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    Effect of circadian rhythm desynchronization on cardiovascular parameters. (A) Similar levels of baseline mean arterial pressure (MAP) and (B) heart rate (HR) in rats in the control (CTR, white bars) and desynchronized (DSC, black bars) groups. (C) The DSC rats show reduced baroreflex sensibility expressed as a bradycardic mean index induced by phenylephrine infusion. (D) The tachycardia mean index induced by sodium nitroprusside did not differ between groups. Results are expressed mean ± s.e.m. *P < 0.05 indicates a significant difference from CTR rats according to an unpaired Student’s t test.

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