Activation of intestinal olfactory receptor stimulates glucagon-like peptide-1 secretion in enteroendocrine cells and attenuates hyperglycemia in type 2 diabetic mice

Abstract

Odorants are non-nutrients. However, they exist abundantly in foods, wines, and teas, and thus can be ingested along with the other nutrients during a meal. Here, we have focused on the chemical-recognition ability of these ORs and hypothesized that the odorants ingested during a meal may play a physiological role by activating the gut-expressed ORs. Using a human-derived enteroendocrine L cell line, we discovered the geraniol- and citronellal-mediated stimulation of glucagon-like peptide-1 (GLP-1) secretion and elucidated the corresponding cellular downstream signaling pathways. The geraniol-stimulated GLP-1 secretion event in the enteroendocrine cell line was mediated by the olfactory-type G protein, the activation of adenylyl cyclase, increased intracellular cAMP levels, and extracellular calcium influx. TaqMan qPCR demonstrated that two ORs corresponding to geraniol and citronellal were expressed in the human enteroendocrine cell line and in mouse intestinal specimen. In a type 2 diabetes mellitus mouse model (db/db), oral administration of geraniol improved glucose homeostasis by increasing plasma GLP-1 and insulin levels. This insulinotropic action of geraniol was GLP-1 receptor-mediated, and also was glucose-dependent. This study demonstrates that odor compounds can be recognized by gut-expressed ORs during meal ingestion and therefore, participate in the glucose homeostasis by inducing the secretion of gut-peptides.

The Effects of Essential Oils and Terpenes in Relation to Their Routes of Intake and Application

“…It has been known from early in the 1990s that olfactory receptors are expressed in non-olfactory tissues, such as sperm cells [53][54][55], testes [55,56], heart [57], kidney [58], skin [59], and gut/intestine [60][61][62]. These olfactory receptors are not involved in sensing odors but are involved in chemical reactions, such as chemotaxis [54], adjusting blood pressure [58], and stimulating secretion of hormones [57] and enzymes [58].…”

“…Studies have also indicated that geraniol, a monoterpene found in various flowers (rose (Rosa), lemon (Citrus limon), lavender (Lavandula angustifolia)) and fruits, and citronellal, which is a monoterpenoid with a strong lemon-like smell, stimulate glucagon-like peptide 1 secretion in mouse intestinal tissues and in cultured enteroendocrine cells [62].…”

“…Since propionate is a ligand of Olfr78, there is a possible role of essential oils in regulating blood pressure [58]. Studies have also indicated that geraniol, a monoterpene found in various flowers (rose (Rosa), lemon (Citrus limon), lavender (Lavandula angustifolia)) and fruits, and citronellal, which is a monoterpenoid with a strong lemon-like smell, stimulate glucagon-like peptide 1 secretion in mouse intestinal tissues and in cultured enteroendocrine cells [62]. In a study using mice, in which geraniol was intraperitoneally injected (thus, not through the digestive system) and responses to acetic acid were measured, geraniol was found to have as strong an analgesic impact as morphine, measured by the latency, to show writhing after intraperitoneal injection of acetic acid [77].…”

The Sensing Liver: Localization and Ligands for Hepatic Murine Olfactory and Taste Receptors

“…In cultured hepatocytes, murine Olfr43 has been shown to reduce hepatic lipid accumulation and adiposity while its human homolog (OR1A1) has been shown to reduce PPAR-γ expression ( Wu et al, 2019 ). Another study found that stimulation of Olfr43 led to the secretion of glucose-like phosphoprotein-1 (GLP-1) in enteroendocrine cells, which in turn helps regulate blood glucose levels in a type-2 diabetic mouse model ( Kim et al, 2017 ). In this study, we were able to confirm full-length expression of Olfr544 which had been previously found in the liver by Wu et al (2017) .…”

Cucurbitacin B Induces Hypoglycemic Effect in Diabetic Mice by Regulation of AMP-Activated Protein Kinase Alpha and Glucagon-Like Peptide-1 via Bitter Taste Receptor Signaling

“…Under OGTT condition, CuB (0.1 mg/kg) orally was administrated in C57BL/6 ( n = 8) or Gα-gust −/− mice ( n = 5). The i.p injection of exendin 9-39 (Ex9, 10 μg/100 ul) or vehicle (PBS, 1% BSA) was performed and incubated for 20 min before OGTT ( Kim et al, 2017c ). The experiments were repeated with the other groups of C57BL/6 mice ( n = 8).…”