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 findings 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 outflow from the hypothalamus toward target organs and thereby influence 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 fight hypertriglyceridemia by specifically modulating sympathetic nervous system outflow toward liver, BAT, or WAT.
Highlights
Important players in triglyceride (TG) metabolism include the liver, white adipose tissue (WAT), heart and skeletal muscle, and brown adipose tissue (BAT), the collective action of which determine plasma TG levels
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]
Bruinstroop et al [28] recently showed that hepatic sympathetic denervation in rats reduced hepatic VLDL-TG secretion. This reduction in VLDL-TG secretion was observed in 19 h-fasted rats but not in postprandial, 4 h-fasted rats. These results indicate that the sympathetic nervous system (SNS) is involved in regulating hepatic VLDL-TG secretion during fasting, a situation in which lipids become the key substrate for energy metabolism [28]
Summary
The various key target organs involved in TG metabolism (i.e., liver, WAT, and BAT) are densely innervated by the sympathetic branch of the autonomic nervous system and are at least in part, controlled by the brain. The major brain region involved in the regulation of general energy balance is the hypothalamus [9, 16]. Within the arcuate nucleus (ARC) of the hypothalamus, two neuronal populations, proopiomelanocortin (POMC)-expressing neurons and neuropeptide Y (NPY)/Agouti-related protein (AgRP)-expressing neurons, oppositely regulate energy metabolism [17]. Activation of POMC neurons leads to the production of ␣-melanocyte-stimulating hormone (␣MSH), which in turn stimulates the melanocortin (MC) receptors within the hypothalamic paraventricular nucleus (PVN) to promote a catabolic state of the body [18]. Stellate ganglia give rise to postsynaptic sympathetic nerve fibers, which subsequently innervate the target organ. Noradrenalin subsequently binds to adrenergic receptors located at the postsynaptic membrane located on the target organ [22]. Each class of adrenergic receptors couples to a different G␣ protein, resulting in different intracellular cascades
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