Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System > 자유게시판

GLP-1 is an incretin that influences energy homeostasis by reducing appetite and food intake and inhibiting gastric emptying (Drucker and MedicGLP Dietary Supplement Nauck, 2006). In the gut a particular group of entero-endocrine cells, L-cells, are responsible for the production of GLP-1 and are predominantly found in the terminal ileum and colon (Drucker and Nauck, 2006; Lim and Brubaker, 2006). The action of bile acids on GLP-1 release is predominantly regulated via TGR5 receptors located at the basolateral membrane of L-cells, thus not facing the lumen of the intestine (Brighton et al., 2015). This means that bile acids first need to cross both the apical and MedicGLP.com the basolateral membrane of intestinal cells in order to activate TGR5 and provoke a GLP-1 response. L-cell GLP-1 release follows a circadian rhythm suggesting it is also under control of the molecular clock system (Gil-Lozano et al., 2014). In addition, GLP-1 release by L-cells can also be triggered via different routes not involving bile acid-induced TGR-5 activation (Lim and Brubaker, 2006). These include indirect routes via endocrine and neural signals induced by the presence of food in the stomach and upper intestine (Lim and Brubaker, 2006; Holst, 2007), stimuli thought to be responsible for the rapid postprandial release of GLP-1 (Holst, 2007). When food reaches the ileum, the GLP-1 producing L cells are directly stimulated by glucose, fat (Lim and Brubaker, 2006; Ezcurra et al., 2013), and bile acids (Katsuma et al., 2005; Thomas et al., 2009). The amplitude of the evoked GLP-1 response depends on meal size (Vilsboll et al., 2003). It is difficult to differentiate between the effects induced by GLP-1 in general and the effects that are particularly induced by GLP-1 as a consequence of TGR5 activation by bile acids.

Research using TGR5 knockout (TGR5−/−) mice showed that these mice still produce GLP-1 and seemed not different from wild type mice (Thomas et al., 2009). However, TGR5−/− mice fed a HFD displayed impaired glucose tolerance compared to wild types (Thomas et al., 2009). This might indicate that under normal circumstances sufficient GLP-1 is released via signaling routes not involving TGR5-activation. However, this TGR5-independent GLP-1 signal might not be proficient under more extreme circumstances e.g., when high amounts of fat are digested. Intestinal GLP-1 can reach the brain via two major routes, one being via the systemic circulation and interacting with GLP-1 receptors in the brain (Orskov et al., 1996; Yamamoto et al., 2003) and the other route being through signaling via the vagus nerve (Abbott et al., 2005; Rüttimann et al., 2009). When GLP-1 is released from the basolateral membrane of the L-cells, GLP-1 is taken up by capillaries and transported to the portal vein and subsequently the liver (Holst, 2007). Nonetheless, only a fraction of intestinal GLP-1 reaches the liver in its active form, because the endothelial membranes of the capillaries express the enzyme dipeptidyl peptidase-4 (DPP-4), MedicGLP Dietary Supplement which degrades GLP-1 rapidly (Holst and Deacon, 2005). Due to the rapid decay only 25% of the intestinal GLP-1 reaches the hepatic portal vein (Holst, 2007). Of this portion only half reaches the systemic circulation via the liver.

The GLP-1 receptor is expressed in various tissues including the CNS (Richards et al., 2014; Cork et al., 2015). GLP-1 is capable of crossing the BBB (Kastin et al., 2002), but it is questionable whether sufficient intact GLP-1 reaches the BBB and other distal tissues to elicit a substantial effect. Therefore, only the area postrema and subfornical area-circumventricular organs-may be plausible brain regions that could gate peripheral GLP-1 signaling via its GLP-1 receptors (Göke et al., 1995; Orskov et al., 1996; Yamamoto et al., 2003). This pathway was established by iv administration of GLP-1 in rats (Orskov et al., 1996; Yamamoto et al., 2003; Punjabi et al., 2014), however, this pathway might not be substantial under normal physiological circumstances when GLP-1 release is triggered by food intake and bile acids. The other pathway through which intestinal GLP-1 could signal to the CNS is via activation of vagal afferent fibers. These sensory fibers originate in the nodose ganglion and provide terminals into peripheral tissues, including liver tissue (Dardevet et al., 2004, 2005), hepatic portal vein (Balkan and Li, 2000; Vahl et al., 2007), and lamina propria of the intestine (Berthoud et al., 2004; Nakagawa et al., 2004). These terminals express GLP-1 receptors and are therefore responsive to local GLP-1 levels (Holst, 2007). The nodose ganglion projects to the nucleus of the solitary tract (NTS) in the hindbrain (Nakagawa et al., 2004; Holst, 2007). NTS neurons are bidirectional connected with other brain regions, including the hypothalamus (Ricardo and Koh, 1978; van der Kooy et al., 1984). In animal models the signal transmission after ip GLP-1 administration was abolished following subdiaphragmatic vagal deafferentation or after transection of the brainstem-hypothalamic pathway (Abbott et al., 2005; Rüttimann et al., 2009). This established the importance of the vagal-brainstem-hypothalamic pathway for the signal transmission of GLP-1 from the gastrointestinal tract to the CNS.

Subsequently, the brainstem and hypothalamus are connected with brain regions involved in autonomic function, metabolic processing, and cognitive and emotional functioning (Rogers et al., 2016). These findings raise the question whether bile acids themselves could directly interact with the vagal nerve and relay a signal to the CNS. However, we have not found reports that show the expression of bile acid receptors on the vagal nerve. Via the vagal-brainstem-hypothalamic pathway peripheral GLP-1 can affect many brain regions and consequently many processes. However, the most studied effects of peripheral GLP-1 are its inhibitory effect on food intake and increased perception of satiety (Tang-Christensen et al., 1996; Turton et al., 1996; Abbott et al., 2005; Talsania et al., 2005; Williams et al., 2006, 2009; Scott and MedicGLP Weight Management Moran, 2007; Hayes et al., 2008; Rüttimann et al., 2009; Punjabi et al., 2014), which are both believed to be mediated predominantly by the CNS (Turton et al., 1996). These data suggest that vagal nerve terminals in the lamina propria of the intestine are involved in regulating appetite.

Postprandial, the highest GLP-1 concentrations are found in the lamina propria of the intestine and second in the hepatic portal vein (Holst and Deacon, 2005; Holst, 2007). GLP-1 signaling via vagal afferents in the hepatic portal vein does not modulate food intake (Rüttimann et al., 2009), but is involved in modulating glucose metabolism by interacting with hepatoportal glucose sensors (Balkan and Li, 2000; Burcelin et al., 2001; Vahl et al., 2007). This reveals a pathway through which bile acids may be capable to modulate glucose metabolism: TGR5-mediated GLP-1 secretion acting upon hepatoportal glucose sensors. Taken together, bile acids in the intestine can signal to the brain by using GLP-1 as an intermediate molecule to activate vagal nerve afferents in the lamia propria and hepatic portal vein that project to the NTS in the hindbrain and subsequently to the hypothalamus. What the exact contribution of bile acids is in the overall GLP-1 signal is difficult to determine, because other nutrient and indirect signals could trigger GLP-1 release.