Rosiglitazone reverses high fat diet-induced changes in BMAL1 function in muscle, fat, and liver tissue in mice

OBJECTIVE: Nutrient 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. METHODS: BMAL1 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. RESULTS: These 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. CONCLUSIONS: This study reveals that a key mechanism by which HF diet interferes with clock function in peripheral tissues is via the development of insulin resistance.