However, in the absence of STZ, twoweek administration of selexipag does not affect -cell mass

s is a precursor PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19793987 to tissue infiltration and their subsequent differentiation into macrophages. These processes are important in regulating the low-grade inflammation that accompanies obesity and in atherogenesis. FFAR2 is also expressed in the L cells of the ileum and colon. These entero-endocrine cells synthesize and secrete peptide YY. The latter is known to be increased in response to shortchain FAs, and its release is accompanied by decreased appetite and decreased food intake through actions in the central nervous system. Short-chain FAs are produced in the gut by microbial fermentation of indigestible carbohydrate. Using probiotics, the gut flora can be altered and this has recently been proposed as a means of regulating appetite, decreasing insulin resistance and decreasing risk of nonalcoholic fatty liver disease. Use of probiotics increases intestinal release of glucagon-like peptide -1 and GLP-2 and also peptide YY. Finally, FFAR2 has been reported to be expressed in adipocytes, and its expression upregulated in mice fed a high fat diet. Silencing of the FFAR2 gene using siRNA interfered with adipocyte differentiation in the 3T3-L1 cell line. These authors did not detect FFAR3 in adipose tissue or 3T3-L1 cells. In our hands, FFAR3 is highly expressed in 3T3-L1 preadipocytes and adipocytes, while FFAR2 is only expressed in fully differentiated cells. Ge and colleagues reported that FFAR2 activation decreased lipolysis in vivo, an effect that was not present in FFAR2 knockout mice. Furthermore, in vivo FFAR2 activation decreased plasma FFA levels. Clearly, FFAR2 activation could improve some features of metabolic syndrome. However, as with thiazolidinediones, this may be achieved by decreasing circulating FFAs through increased adipocyte differentiation and thus increased levels of adiposity. Lee and colleagues described a number of small molecule phenylacetamides that acted as selective allosteric agonists at FFAR2. The synthetic ligands were more potent than endogenous ligands, and treatment of adipocytes with these agonists inhibited lipolysis. FFAR3 Propionate, butyrate and pentanoate are all equally potent in activating FFAR3, which couples with Gai/o. GPR42 shares 98% homology with FFAR3 but is biologically inactive. Xiong and colleagues reported that FFAR3 was highly expressed in both an adipocyte cell line and primary adipocyte cultures. Propionate, CJ-023423 web acting through FFAR3, increased leptin secretion by adipocytes and propionate administration to mice increased circulating leptin levels. Short-chain FAs may thus regulate appetite and energy homeostasis through FFAR3 expressed on adipocytes. Previous studies suggested that FFAR2 but not FFAR3 was expressed on mature adipocytes. Clearly this inconsistency, which may arise from use of different cell and animal models in different studies, needs to be resolved. To date, small molecule synthetic ligands for FFAR3 have not been described. FFAR2 and FFAR3 have about 50% structural homology. Their relative importance and their differing physiological http://tae.sagepub.com 167 Therapeutic Advances in Endocrinology and Metabolism 1 roles are poorly understood. There is, however, considerable interest currently in the regulatory effects of short-chain FA in nutrient intake, energy balance, glucose homeostasis and cardiovascular risk: modest alcohol intake decreases risk of cardiovascular events through improved lipid profile and glucose tolerance as well as having beneficial effects