Understanding the role of vagal FFAR3 in regulating glucose homeostasis

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PROJECT SUMMARY/ABSRACT The goal of this F31 application is to elucidate the roles and mechanisms of FFAR3 signaling in the vagus nerve in regulating glucose homeostasis. Proper regulation of energy metabolism requires sensing of nutrient and hormonal cues to coordinate an appropriate behavioral and physiological response. Vagus nerve sensing of dietary nutrients or nutrient-stimulated hormones has been demonstrated to regulate food intake, glucose homeostasis, and gut motility. The gut microbiome ferments soluble non-digestible fiber to release short-chain fatty acids (SCFA’s) which can serve as signaling molecules through G-protein coupled receptors. The SCFA’s, including acetate, propionate, and butyrate can bind free fatty acid receptor 2 (FFAR2) and 3 (FFAR3). Increasing dietary fiber intake or directly supplementing SCFA’s has been shown to improve host glucose homeostasis, but the molecular mechanisms mediating these effects are unclear. Direct vagal sensing of gut microbiome produced SCFA’s via FFAR3 could contribute to regulation of glucose metabolism. We found that propionate was decreased in the plasma of western diet (WD)-fed mice compared to normal chow (NC)-fed controls. When obese mice received oral gavages of fecal microbiome transplantations (FMT) from lean NC-fed donors, their plasma propionate levels increased, and fasting blood glucose decreased. Directly supplementing propionate in the water of WD- fed mice lowered fasting glucose and improved glucose tolerance. Propionate is the most potent known endogenous ligand for FFAR3, and FFAR3 KO mice exhibit disrupted glucose tolerance, so we hypothesized that FFAR3 expressed on the vagus nerve connects microbiome-produced propionate and central nervous system control of glucose homeostasis. Indeed, we found Ffar3 to be actively translated in vagal sensory neurons. Treatment of vagal cultures with the FFAR3 ligand, propionate, activated the neurons and increased neuronal translation of Glp1r. Vagal GLP1R function and expression is dysregulated in rodent models of obesity, but the molecular mechanisms are not well understood. We hypothesize that propionate signals through FFAR3 in the vagus nerve to increase Glp1r expression and improve glucose homeostasis. We will test this hypothesis through the following aims. Aim 1 will assess if propionate activates vagal neurons and increases Glp1r translation via FFAR3 in vagal organotypic cultures. We will accomplish this by utilizing the ribotag genetic mouse model which allows for cell-specific assessment of genes in translation. We will assess translation of glucoregulatory genes after propionate stimulation in vagal ganglia expressing FFAR3, and ganglia from FFAR3KO mice. Aim 2 will assess whether vagal FFAR3 is required for propionate to improve glucose intolerance in vivo in WD-fed male and female mice. To accomplish this, we will utilize a novel FFAR3 floxed mouse model and genetically ablate FFAR3 only from vagal neurons. We will challenge control and vagal FFAR3KO mice with a western diet, supplemented with either saline or propionate, to determine if propionate improves WD-induced glucose intolerance via FFAR3. Overall, we expect this study to improve the understanding of how propionate and FFAR3 contribute to autonomic control of glucose homeostasis and energy balance. The proposed study will elucidate new signaling pathways for the treatment of type 2 diabetes.