Free fatty acid receptor activation alters mesenteric lymphatic flow and fatty acid transport in rats

Abstract

Enteroendocrine cells express nutrient GPCRs and release gut hormones in response to luminal nutrients. Free fatty acid receptors (FFARs) are activated by luminal long-chain (LCFAs) or short-chain fatty acids (SCFAs). We hypothesized that activation of FFARs may alter lipid absorption. Lymph was collected via mesenteric lymph duct cannulation in anesthetized rats. We examined the effect of bolus perfusion of selective FFAR agonists (10 µM) into the duodenum on lymphatic flow. Fatty acid transport was assessed by in vivo microscopy and by the appearance rate of fluorescent-conjugated LCFA probe (C1-BODIPY-C12 (BDPY), equivalent to C18 oleic acid) into lymph. Luminal BDPY was quickly absorbed by duodenal and jejunal villous cells. Luminal BDPY (25 µM) increased the lymphatic flow rate and was transported into lymph. The CD36 inhibitor sulfosuccinimidyl oleate reduced BDPY transport rate, confirming that BDPY functioned as a LCFA. The selective FFA1 agonist GW9508 enhanced the lymphatic flow rate and BDPY transport, accompanied by glucagon-like peptide-2 (GLP-2) release into lymph. GLP-2 receptor antagonism abolished the GW9508-induced increase of lymphatic flow and BDPY transport. In contrast, the selective FFA2 agonist increased BDPY transport via 5-HT3 activation, consistent with FFA2 expression on EC cells. The selective FFA4 agonist had little effect on lymphatic flow or on BDPY transport. Respective release of GLP-2 and 5-HT via FFA1 and FFA2 activation alters LCFA transport during lipid absorption. Luminal FFARs may be therapeutic targets for obesity and 5-HT-related dyspeptic symptoms. Supported by VA Merit Review, NIH R01 DK54221