Maaike van Buuren1, Robin van Eenige1, Eric Kalkhoven2, Patrick Rensen1, Sander Kooijman1
(1) Division of Endocrinology, Department of Medicine, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands.
(2) Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands.
PPARγ is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance and hyperlipidemia. We previously showed that adipose tissue is highly rhythmic and identified PPARγ as a potential regulator of the circadian transcriptome. Here, we studied whether PPARγ agonism with rosiglitazone exerts differential effects on lipid levels dependent on the time of administration.
Male C57BL/6J mice were fed a high-fat diet (45 kcal%) and received a daily oral gavage with rosiglitazone (10 mg/kg) or vehicle for five weeks at Zeitgeber time (ZT)10 or ZT22. Body weight and composition were monitored and plasma triglyceride, glucose, and insulin levels were determined throughout the intervention. At the end of the study, uptake of radio-labeled triglyceride-derived fatty acids by adipose tissue was assessed.
Rosiglitazone treatment delayed body weight gain independent of timing of administration. Despite similar body weight and body composition at endpoint, mice treated with rosiglitazone treatment at ZT10 showed a pronounced reduction in plasma triglyceride levels (-23%). This coincided with an increased uptake of triglyceride-derived fatty acids by brown adipose tissue (+50%) and a non-significant increase in the uptake by white adipose tissue (+43%), effects that were not observed with treatment at ZT22. Similarly, only rosiglitazone treatment at ZT10 decreased insulin levels (-32%) and improved insulin resistance (HOMA-IR -47%).
PPARγ agonism exerts differential effects on glucose and lipid metabolism depending on timing of administration to mice. Current research focuses on the consequences for therapeutic application of TZDs in cardiometabolic diseases.