n and matrix metalloproteinase-9 release, in an i -dependent manner. In taste buds, GPR40 plays a critical role in the taste response to nutritional sensing of LCFAs; the Acacetin site receptor is primarily expressed on the back of the tongue, including on the circumvallate and foliate papillae. Although further studies are needed to clarify the function of GPR40 in taste buds, these findings suggest that GPR40 has a key role in the perception of a lipid taste. GPR40 is also widely expressed in the central nervous system, including in neurons of the cerebral cortex, hippocampus, amygdala, hypothalamus, cerebellum and spinal cord. Activation of GPR40 in neuroblastoma cells induced the phosphorylation of cAMP response element-binding protein and ERK1/2; the former may influence the secretion of brain-derived neurotrophic factor, which plays an important role in activity-dependent regulation of synaptic structure and function. TAK-875, a potent and selective small-molecule agonist of GPR40, is useful for the development of the treatment for T2D by Takeda. 3. GPR120/FFAR4 GPR120 is a receptor for MC- and LCFAs that stimulates GLP-1 secretion from L cells in the colon and is activated by various -3 or -6 polyunsaturated fatty acids, including docosahexaenoic acid C22:6 and eicosapentaenoic acid C20:5, at micromolar concentrations. However, GPR120 is strongly activated by -linolenic acid C18:3 . Although the ligands’ affinity is similar to those of GPR40, the two receptors share only 10% amino acid homology. LCFAs increased i, but exerted no effects on cAMP production in human or mouse GPR120-expressing cells, indicating that GPR120 is coupled with the Gq protein family, but not with the Gi/o or Gs protein families. In addition, GPR120 activates ERK1/2 and phosphoinositide 3-kinase, although the underlying mechanisms remain unclear. Int. J. Mol. Sci. 2016, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19818716 17, 450 4 of 12 GPR120 is widely expressed in many tissues and cell types, such as the intestine, pancreas, adipocytes and immune cells. This suggests that GPR120 has varied roles in energy regulation and immunological homeostasis. GPR120 activation by DHA had anti-inflammatory effects in macrophages associated with the suppression of Toll-like receptor signaling via the -arrestin-2 and with the inhibition of transforming growth factor–activated kinase 1, which is involved in pro-inflammatory tumor necrosis factor – signaling. Thus, GPR120 is an -3 FFA receptor that improves insulin resistance and anti-diabetic effects by suppressing tissue inflammation mediated by macrophages. Moreover, stimulation of FFAs induced GLP-1 and CCK secretion in mouse enteroendocrine STC-1 cells, as a murine enteroendocrine cell line,, while Gpr120 knockdown abolished FFA-induced effects on incretin secretion and i levels. The effect of 
FFAs on the plasma levels of GLP-1 and insulin were examined by the administration of FFAs into the mouse colon. The lipid accumulation during the adipogenesis in 3T3-L1 cells, as a murine preadipocyte cell line, induced GPR120 expression, and Gpr120 knockdown in 3T3-L1 cells and the embryonic fibroblasts in Gpr120 deficient mice inhibited the adipogenic gene expressions and prevented lipid accumulation. These findings indicate that GPR120 plays an important role in the differentiation and maturation of adipocytes. In humans, GPR120 dysfunction leads to obesity, resulting in glucose intolerance and fatty liver accompanied by decreased adipocyte differentiation and lipogenesis and enhanced he
