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

ABSTRACT: 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.

SUBMITTER: Ribas-Latre A

PROVIDER: S-EPMC6351224 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND AND PURPOSE: ??-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)? agonist rosiglitazone modulated salbutamol-induced ??-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH: An in vivo model of homologous ??-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent ??-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS: In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of ??-adrenoceptor gene and a marked decrease in ?-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored ??-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPAR? agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro ??-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and ??-adrenoceptor expression. Rosiglitazone and 15-deoxy-?¹²(,)¹?-prostaglandin J? restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential pharmacodynamic interaction between PPAR? agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.

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

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