br Gastrointestinal peptides and intestinal health

Gastrointestinal peptides and intestinal health Gastrointestinal peptides are intimately involved in the regulation of feeding behaviors, energy metabolism and bodyweight 36, 37, 38, 39, 40, 41. GPR120 has been demonstrated to induce secretion of two such peptides: GLP-1 and cholecystokinin (CCK), from enteroendocrine STC-1 yohimbine hydrochloride in vitro6, 9, 10. In both instances, transient knockdown of GPR120 ablated the effect of α-LA on secretion of GLP-1 and CCK, to confirm that GPR120 is indeed responsible for this effect 6, 9. GLP-1 is an insulinotropic, anorectic peptide that reduces gastric emptying and motility 37, 38. Like GLP-1, CCK regulates a diverse range of local and distal physiological effects including promotion of pancreatic secretions, gallbladder contractions, inhibition of gastric motility and secretions, and reduces energy intake [42]. Curiously, GPR120 has also been shown to co-localize with the orexigenic peptide, ghrelin in duodenal cells in vivo and α-LA reduces ghrelin secretion in the MGN3-1 ghrenlinoma cell line [43]. However, this effect persisted in cells transfected with siRNAs targeting GPR120, which indicates GPR120 was not mediating this effect. Further studies that confirm these results would be of interest given that decreased appetite, which accompanies reductions in ghrelin [44], could provide an adjunctive mechanism by which GPR120 has favorable effects on systemic energy homeostasis. As the current indication of the cumulative effects GPR120 agonism has on the secretion of GLP-1 CCK and ghrelin levels, this could culminate in enhanced glycemia, improved appetite control and improved overall energy homeostasis. Beyond a role in mediating the secretion of gastrointestinal peptides, Fredborg et al.[45] showed that GPR120 mRNA expression is increased in intestinal Caco-2 cells by cultured medium from bacteria of the Bacteroidetes and Firmicutes phyla. Dietary composition (such as high fat and alcohol intakes) and obesity can lead to dysbiosis and alter the ratio of intestinal-bacteroidetes:firmicutes 46, 47, 48, 49. This suggests another mechanism whereby GPR120 expression and subsequently function could be upregulated. In contrast to these beneficial effects, Wu et al.[16] recently identified an oncogenic potential for GPR120 in promoting tumorigenesis in colorectal cancers. This study is the first to examine a role for GPR120 in cancer progression but reveals interesting findings with GPR120 mediating pro-angiogenic signaling and promoting chemotaxis in tumor cell lines in vitro, which was supported by in vivo findings showing that GPR120 activation promoted angiogenesis and tumor growth in mice [16]. Although further studies are needed to investigate the effects of GPR120 in carcinogenesis, these data support GPR120 agonism as exerting a cancer-promoting effect, suggesting that applications for GPR120 agonists in intestinal tissues should be approached with caution.
Spontaneous taste preference Hedonia is a major determinant of dietary intake to which taste is intimately linked [50]. Lipid-rich foods are typically highly palatable and energy dense [50]. This palatability predisposes to excessive consumption of lipid-rich foods that, owing to the high energy density, contribute greatly to daily caloric intake. Thus, chronic overconsumption of lipid-rich foods can increase bodyweight and facilitate the development of obesity and associated co-morbidities. GPR120 is expressed in cells responsible for detecting taste including those of the circumvallate, foliate and fungiform papillae [51]. Cartoni et al.[51] provide evidence of a role for GPR120 in mediating spontaneous preference for palatable high fat foods, with GPR120−/− mice exhibiting ambivalence toward dietary FAs compared with preferential intake of FAs in wild-type animals. This suggests that aberrant upregulation of GPR120 activity in taste bud cells could foster an increased intake of dietary lipid. Godinot et al.[52] also provide a role for GPR120 and GPR40 in mediating innervation of the glossopharyngeal nerve, indicating an ability to regulate taste. However this paper argues a greater role for GPR40 in mediating taste response to FAs, with GPR40 agonists provoking a ‘fatty’ taste in human subjects, whereas the GPR120 agonists did not [52]. Although further work is needed to delineate the role of GPR120 in mediating taste preference, it is interesting to note that GPR120 expression in the circumvallate papillae was unaffected by dietary lipid content and type, fasting or the diurnal state [53], suggesting that GPR120 is likely to have a relatively stable influence on dietary lipid intake.