Abstract
ObjectiveNutrient challenge in the form of a high fat (HF) diet causes a reversible reprogramming of the hepatic circadian clock. This depends in part on changes in the recruitment of the circadian transcription factor BMAL1 to genome targets, though the causes and extent of disruption to hepatic and extra-hepatic BMAL1 are unknown. The objective of the study was to determine whether HF diet-induced alterations in BMAL1 function occur across insulin-resistant tissues and whether this could be reversed by restoring whole body insulin sensitivity.MethodsBMAL1 subcellular localization and target recruitment was analyzed in several metabolically active peripheral tissues, including liver, muscle, and adipose tissue under conditions of diet-induced obesity. Animals made obese with HF diet were subsequently treated with rosiglitazone to determine whether resensitizing insulin-resistant tissues to insulin restored hepatic and extra-hepatic BMAL1 function.ResultsThese data reveal that both hepatic and extra-hepatic BMAL1 activity are altered under conditions of obesity and insulin resistance. Restoring whole body insulin sensitivity by treatment with the antidiabetic drug rosiglitazone is sufficient to restore changes in HF diet-induced BMAL1 recruitment and activity in several tissues.ConclusionsThis study reveals that a key mechanism by which HF diet interferes with clock function in peripheral tissues is via the development of insulin resistance.
Highlights
Circadian rhythms are evident in almost every aspect of physiology
Our results reveal that high fat (HF) diet alters BMAL1 recruitment and activity in the liver and in the muscle and white adipose tissue, and that antidiabetic treatment that restores whole body insulin sensitivity is able to reverse the aberrant BMAL1 activity in these tissues
To determine whether altered BMAL1 function under nutrient challenge conditions is affected across insulinsensitive metabolic tissues, mice were fed with CD or HF diet for over 10 weeks to induce obesity
Summary
To determine whether altered BMAL1 function under nutrient challenge conditions is affected across insulinsensitive metabolic tissues, mice were fed with CD or HF diet for over 10 weeks to induce obesity. While ROSI has been shown to alter circadian hepatic gene expression [33], we wished to determine whether restoring insulin sensitivity in HF-fed mice is sufficient to restore BMAL1 target recruitment. To determine whether restoring insulin sensitivity by ROSI was sufficient to restore BMAL1 target recruitment in the livers of HF-fed mice, the BMAL1 target genes, Dbp, Fabp, and Chrono were analyzed for changes in expression. To determine whether altered gene expression was a result of changes in BMAL1 recruitment, ChIP was performed on livers of chow and HF-fed mice treated with vehicle or ROSI. As for hepatic BMAL1 recruitment, administration of HF diet with ROSI reversed the HF diet-induced BMAL1 binding to target E boxes in SC WAT (Fig. 4e), suggesting that a key mechanism by which diet controls peripheral BMAL1 function in adipose tissue, muscle, and liver is through feeding-induced changes in insulin sensitivity
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