Aims/hypothesisGlucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT.MethodsLean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions.ResultsCentral administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.Conclusions/interpretationCollectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

Dyslipidemia is one of the classical risk factors for cardiovascular diseases (CVD) besides hypertension, type 2 diabetes, and smoking ( 1 ). Dyslipidemia is defi ned as an elevation of plasma LDL-cholesterol (LDL-C), triglycerides (TG), or both, with or without a lowering of HDLcholesterol (HDL-C) ( 2 ). Whereas elevated LDL-C is a well-established major predictor of CVD and has been the primary target for lipid-lowering strategies, evidence suggests that an elevated TG level is an independent risk factor for CVD development as well ( 3, 4 ). Plasma TG levels are considered elevated when they exceed 150 mg/dl, which is observed in 31% of the adult US population ( 5 ). Although hypertriglyceridemia can be caused by rare monogenic disorders, it is mostly caused by a complex interaction between environmental factors and subtle variations in genes involved in lipoprotein metabolism ( 5 ). Current treatments for hypertriglyceridemia are aimed at either increasing TG clearance (e.g., fi brates) ( 6 ) or at decreasing lipolysis in WAT (e.g., niacin) ( 7 ). In addition, reduction of VLDL-TG production lowers plasma TG levels (e.g., exendin-4) ( 8 ).In recent years, the autonomic nervous system, which consists of a sympathetic and a parasympathetic branch, emerged as an important regulator of metabolic homeostasis. Whereas the role of the sympathetic nervous system (SNS) in the regulation of glucose metabolism has been fi rmly established (for review, see Ref. 9 ), considerably fewer studies have focused on its role in TG metabolism. This review provides an update specifi cally on the role of Abstract Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent fi ndings in the area of sympathetic control of TG metabolism. Various neuronal populations, such as neuropeptide Y (NPY)-expressing neurons and melanocortin-expressing neurons, as well as peripherally produced hormones (i.e., GLP-1, leptin, and insulin), modulate sympathetic outfl ow from the hypothalamus toward target organs and thereby infl uence peripheral TG metabolism. We conclude that sympathetic stimulation in general increases lipolysis in WAT, enhances VLDL-TG production by the liver, and increases the activity of BAT with respect to lipolysis of TG, followed by combustion of fatty acids toward heat. Moreover, the increased knowledge about the involvement of the neuroendocrine system in TG metabolism presented in this review offers new therapeutic options to fi ght hypertriglyceridemia by specifi cally modulating sympathetic nervous system outfl ow toward liver, BAT, or WAT .-Geerling, J. J., M. R. B...