Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine

Abstract

Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G-protein-coupled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we examined the effect of FFAR1 activation on GLP-1 secretion using isolated, perfused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 agonists (TAK-875, AMG 837, AM-1638, and AM-5262) were administered through intraluminal and intra-arterial routes, respectively, and dynamic changes in GLP-1 secretion were evaluated. Vascular administration of 10 μmol/L TAK-875, 10 μmol/L AMG 837, 1 μmol/L and 0.1 μmol/L AM-1638, 1 μmol/L AM-6252, and 1 mmol/L LA, all significantly increased GLP-1 secretion compared to basal levels (P < 0.05), whereas luminal administration of LA and FFAR1 agonists was ineffective. Thus, both natural and small-molecule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion, indicating that therapies based on activation of nutrient sensing may be more complex than hitherto expected.

Complex Pharmacology of Free Fatty Acid Receptors

“…2,13 Interestingly, however, a recent study found that while LCFAs do stimulate GLP-1 release from the rat small intestine, this was only observed when the LCFA was administered via the vasculature and not when administered via the intestinal lumen. 146 Although a limited observation from a single study, this surprising result suggests a need to absorb the LCFA in order to produce the effect on GLP-1 release. If confirmed, this is likely to have significant implications as to how FFA1 functions as a nutrient sensor and, indeed, if and how it will be possible to manipulate FFA1 function through diet.…”

Roles of the Gut in Glucose Homeostasis

“…Detection of ingested fat, by contrast, seems to largely depend on G-protein-coupled receptors (GPRs) that detect the triacylglycerol digestion products, fatty acids (sensed by GPR40 and GPR120), and monoacylglycerols (sensed by GPR119) (60). Of note, GPR40-dependent fatty acid detection by L cells also seems to depend on the rate of nutrient absorption, as intestinal perfusion experiments have indicated that the receptor is accessible from the basolateral rather than luminal direction (67). Although close apposition of enteroendocrine cells with the terminals of enteric neurons has been described, the physiological role of neuronal signals in regulating gut hormone secretion remains uncertain (15).…”

Expression and function of umami receptors T1R1/T1R3 in gastric smooth muscle

“…3,33 For example, a free fatty acid receptor 1 (FFAR1) agonist did not affect intestinal secretory functions when administered intraluminally, but induced GLP-1 release after intravascular administration. While we did not evaluate the systemic effect of MSG and MSG plus IMP, absorption of nutrients can have stimulatory effects via the vasculature that differs from direct interaction in the gut lumen.…”