Free fatty acid receptor 3 is a key target of short chain fatty acid

Abstract

Nervous system (NS) activity participates in metabolic homeostasis by detecting peripheral signal molecules derived from food intake and ene rgy balance. High quality diets are thought to include fiber-rich food s like whole grain rice, breads, cereals, and grains. Several studies have associated high consumption of fiber-enriched diets with a reduce d risk of diabetes, obesity, and gastrointestinal disorders. In the lo wer intestine, anaerobic fermentation of soluble fibers by microbiota produces short chain fatty acids (SCFAs), key energy molecules that ha ve a recent identified leading role in the intestinal gluconeogenesis, promoting beneficial effects on glucose tolerance and insulin resista nce1. SCFAs are also signaling molecules that bind to specific G-prote in coupled receptors (GPCRs) named Free Fatty Acid Receptor 3 (FFA3, G PR41) and 2 (FFA2, GPR43). However, how SCFAs impact NS activity throu gh their GPCRs is poorly understood. Recently, studies have demonstrat ed the presence of FFA2 and FFA3 in the sympathetic NS of rat, mouse a nd human2, 3. Two studies have showed that FFA3 activation by SCFAs in creases firing and norepinephrine (NE) release from sympathetic neuron s3, 4. However, the recent study from the Ikeda Laboratory2 revealed t hat activation of FFA3 by SCFAs impairs N-type calcium channel (NTCC) activity, which contradicts the idea of FFA3 activation leading to inc reased action potential evoked NE release. Here we will discuss the sc ope of the latter study and the putative physiological role of SCFAs a nd FFAs in the sympathetic NS.