Activation of brown adipose tissue (BAT) with the 133-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is... Show moreActivation of brown adipose tissue (BAT) with the 133-adrenergic receptor agonist CL316,243 protects mice from atherosclerosis development, and the presence of metabolically active BAT is associated with cardiometabolic health in humans. In contrast, exposure to cold or treatment with the clinically used 133-adrenergic receptor agonist mirabegron to activate BAT exacerbates atherosclerosis in apolipoprotein E (ApoE)-and low-density lipoprotein receptor (LDLR)-deficient mice, both lacking a functional ApoE-LDLR pathway crucial for lipopro-tein remnant clearance. We, therefore, investigated the effects of mirabegron treatment on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a humanized lipoprotein metabolism model with a functional ApoE-LDLR clearance pathway. Mirabegron activated BAT and induced white adipose tissue (WAT) browning, accompanied by selectively increased fat oxidation and attenuated fat mass gain. Mirabegron increased the uptake of fatty acids derived from triglyceride (TG)-rich lipoproteins by BAT and WAT, which was coupled to increased hepatic uptake of the generated cholesterol-enriched core remnants. Mirabegron also promoted hepatic very low-density lipoprotein (VLDL) production, likely due to an increased flux of fatty acids from WAT to the liver, and resulted in transient elevation in plasma TG levels followed by a substantial decrease in plasma TGs. These effects led to a trend toward lower plasma cholesterol levels and reduced atherosclerosis. We conclude that BAT activation by mirabegron leads to substantial metabolic benefits in APOE*3-Leiden.CETP mice, and mirabegron treatment is certainly not atherogenic. These data underscore the importance of the choice of experimental models when investigating the effect of BAT activation on lipoprotein metabolism and atherosclerosis. Show less
Aims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing... Show moreAims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.MethodsIn a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.ResultsThe core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.Conclusions/interpretationDiurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.Data availabilityThe raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674). Show less
As the obesity epidemic is still increasing, strategies to prevent and treat obesity and related pathologies are in great demand. Obesity-induced inflammation is thought to contribute to the... Show moreAs the obesity epidemic is still increasing, strategies to prevent and treat obesity and related pathologies are in great demand. Obesity-induced inflammation is thought to contribute to the development of metabolic disorders. Therefore, inflammatory pathways that play a role in obesity-induced inflammation are potential promising targets in the treatment of metabolic disorders. Extensive knowledge on obesity-induced inflammation and the role of inflammatory pathways in the development of metabolic disorders can benefit the development of these therapeutic strategies. Mouse models are widely used to study obesity and related disorders, however, to what extent mouse-derived results translate to humans has not been studied extensively yet. Obesity-induced inflammation and its role in the development of insulin resistance, as well as the similarities of these processes between humans and mice, have been addressed in this thesis. The new findings described in this thesis will be summarized and discussed in the final chapter. Additionally, clinical implications of obesity-induced inflammation as target to treat metabolic disorders and future perspectives will be addressed. Show less
Beek, L. van; Klinken, J.B. van; Pronk, A.C.M.; Dam, A.D. van; Dirven, E.; Rensen, P.C.N.; ... ; Harmelen, V. van 2015
This thesis describes the role of the brain in the regulation of peripheral triglyceride metabolism, in the context of the metabolic syndrome. Based on various pharmacological studies we described... Show moreThis thesis describes the role of the brain in the regulation of peripheral triglyceride metabolism, in the context of the metabolic syndrome. Based on various pharmacological studies we described the role of two hormones, insulin and glucagon-like peptide-1, in the production and clearance of triglycerides. We showed that insulin stimulates the uptake of (triglyceride-derived) fatty acids and that the brain plays an essential role in this process. Additionally, we showed that the glucagon-like peptide-1 receptor analogue exendin-4 decreases triglyceride production by the liver, albeit that the brain does not seem to be involved in this effect. Furthermore, we unraveled the mechanism underlying the effects of metformin, the first-line drug used to treat Type 2 Diabetes, on triglyceride metabolism. We showed that metformin lowers plasma triglyceride levels by stimulating the uptake and subsequent oxidation of triglycerides by the brown adipose tissue, and herewith provided new therapeutical opportunities for this drug. Finally, we showed that apolipoprotein A5, a stimulator of triglyceride hydrolysis and subsequent clearance from the plasma, plays a role in the central regulation of food intake, and herewith described a novel function for this apolipoprotein. Show less
