Diurnal Variation in Vascular and Metabolic Function in Diet-Induced Obesity

Abstract

Circadian rhythms are integral to the normal functioning of numerous physiological processes. Evidence from human and mouse studies suggests that loss of rhythm occurs in obesity and cardiovascular disease and may be a neglected contributor to pathophysiology. Obesity has been shown to impair the circadian clock mechanism in liver and adipose tissue but its effect on cardiovascular tissues is unknown. We investigated the effect of diet-induced obesity in C57BL6J mice upon rhythmic transcription of clock genes and diurnal variation in vascular and metabolic systems. In obesity, clock gene function and physiological rhythms were preserved in the vasculature but clock gene transcription in metabolic tissues and rhythms of glucose tolerance and insulin sensitivity were blunted. The most pronounced attenuation of clock rhythm occurred in adipose tissue, where there was also impairment of clock-controlled master metabolic genes and both AMPK mRNA and protein. Across tissues, clock gene disruption was associated with local inflammation but diverged from impairment of insulin signaling. We conclude that vascular tissues are less sensitive to pathological disruption of diurnal rhythms during obesity than metabolic tissues and suggest that cellular disruption of clock gene rhythmicity may occur by mechanisms shared with inflammation but distinct from those leading to insulin resistance.

Circadian regulation of metabolism

“…Diet-induced obesity, from unrestricted access to a high fat diet, altered rhythms in circadian behaviors (activity and feeding), neuropeptides in the hypothalamus, and clock and metabolism gene expression in liver and adipose tissue of mice (Kohsaka et al 2007). Other studies have reported similar findings in response to diet-induced obesity in highly metabolic tissues (Bravo, et al 2014; Lizier, et al 2013; Pendergast, et al 2013; Prasai, et al 2013; Shi, et al 2013). Recent work by Sassone-Corsi and colleagues also shows that a high fat diet disrupts normal circadian oscillations of the molecular clock and clock-controlled metabolites and transcripts in the liver (Eckel-Mahan, et al 2013); they propose that these high fat diet-mediated alterations in metabolism are linked to impaired CLOCK-BMAL1 chromatin recruitment and induction of peroxisome proliferator-activated receptor gamma (PPARγ)-mediated oscillations in noncyclic genes (Eckel-Mahan et al 2013).…”

Loss of circadian rhythm of circulating insulin concentration induced by high-fat diet intake is associated with disrupted rhythmic expression of circadian clock genes in the liver

“…F-values in the two-way ANOVA are frequently used to assess variances of genes in circadian rhythm [25,26]. Student's t-test was used to compare weights of body tissues and protein concentrations.…”

Therapeutic interventions to reduce the risk of progression from prediabetes to type 2 diabetes mellitus

“…On the other hand, intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risk for the exposed offspring of obesity, metabolic and cardiovascular diseases, and earlier development of T2DM 27,28. Disruption of the circadian rhythm occurs in obesity, diabetes, and cardiovascular disease and is another factor that increases risk for diabetes 29. Transcriptional alterations of the circadian locomotor output cycles kaput (CLOCK) genes in metabolic tissues lead to blunting of rhythms of glucose tolerance and insulin sensitivity 30.…”