est in them owing to their beneficial metabolic effects on glucose homeostasis, food intake, insulin sensitivity and body weight. SCFAs, such as acetate, propionate and butyrate, are produced by gut microbial fermentation of dietary fibers. Gut microbiota affect host nutrient acquisition and energy regulation and can influence the development of obesity and diabetes. Dietary fiber intake reduces the development of various diseases, such as inflammatory and metabolic disorders. Therefore, SCFAs have been proposed to play a key role in the prevention and treatment of inflammatory and metabolic disorders; for instance, butyrate derived from fibers improved insulin sensitivity and increased energy expenditure in a mouse model of diet-induced obesity. FFA receptors are expressed in various tissues and influence many important metabolic functions that maintain energy homeostasis. Several orphan G protein-coupled receptors have been identified as FFARs; SCFAs can activate GPR41/FFAR3 and GPR43/FFAR2, while MC- and LCFAs can activate GPR40/FFAR1 and GPR120/FFAR4 . These FFARs have the potential as new drug targets for metabolic diseases, such as T2D and obesity. 2. GPR40/FFAR1 GPR40 is a receptor for MCFAs and LCFAs and is reported to bind with Gq protein. GPR40 activation increases i and activates the extracellular signal-regulated kinases signaling cascade. Gq protein is a heterotrimeric G protein subunit that activates phospholipase C and then, intracellular Ca2+ release. On the other hand, it also increases cyclic AMP levels via a 71939-50-9 Gs-coupled pathway. MCFAs and LCFAs activate GPR40 at micromolar concentrations; docosahexaenoic acid C22:6 and eicosapentaenoic acid C20:5 are the most potent agonist of GPR40. Interestingly, GPR40 activation by saturated FAs depends on carbon chain length, with palmitic acid identified as potent ligands with high affinity for GPR40. GPR40 is abundantly expressed PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19820012 in pancreatic insulin-producing cells and the intestine. LCFAs promote glucose-stimulated insulin secretion in pancreatic cells, and the specific and acute effects of FFAs were mitigated by the loss of GPR40 function. Acute and chronic effects of FFAs on insulin secretion have been investigated using Gpr40-deficient and pancreatic cell-specific Gpr40 transgenic mice; the chronic effects of LCFAs on GSIS were attenuated in the Gpr40-deficient mice, whereas GPR40 overexpression in pancreatic cells prevented and improved insulin sensitivity in high fat diet -induced obese mice. Furthermore, acute and chronic effects of palmitic acid on insulin sensitivity exerted in part via GPR40 have been reported. The downregulation of GPR40 mRNA 
by exendin-4 suppressed c-Jun N-terminal kinase and mitogen-activated protein kinase cascade, blocking palmitic acid-induced apoptosis in pancreatic cells, while glucose and FFAs in the pancreas have been shown to regulate GPR40 protein level.Hence, LCFAs directly activate GPR40 and enhance GSIS not only by direct stimulation of insulin secretion from pancreatic cells, but also indirectly via upregulation of GLP-1, GIP and CCK in the intestine. In addition, in Caco-2 cells, as a human intestinal epithelial cell line, GPR40 signaling induced by a gut microbial metabolite of linoleic acid restored intestinal epithelial barrier impairments. GPR40 is also expressed in bovine neutrophils. The selective GPR40 agonist GW9508 can modulate bovine neutrophil responses, such as ERK1/2 phosphorylation, superoxide production, CD11b expressio