FRI012 Exploring The Role Of FFA2 In Western Diet-induced Obesity And Metabolic Changes

Disclosure: C. Nnyamah: None. B. Wicksteed: None. B.T. Layden: None. The obesity pandemic is a major health concern driving Type 2 Diabetes (T2D) and cardiovascular disease (CVD). One novel pathogenetic factor of obesity is the gut microbiome (GM), that is the microbes that reside in the digestive tract. Changes in the GM have profound effects on obesity. These symbiotic microbes break down dietary fiber that are otherwise indigestible, releasing nutrients (in particular, short chain fatty acids, SCFAs). Free Fatty Acid Receptor 2 (FFA2) is a G-protein coupled receptor (GPCR) that senses SCFAs and has been shown to influence the function of various organs responsible for nutrient-sensing and energy balance. Among other roles, FFA2 has been suggested to modulate the secretion of the appetite-regulating proteins GLP-1 and PYY from intestinal enteroendocrine cells and secretion of insulin (the master fuel-supply hormone) from the pancreatic beta cells. However, its role in adipose tissue is less clear. While highly expressed in adipose tissue, research using global knockouts (KOs) of FFA2 in mouse models has observed conflicting phenotypic results. Here, we use novel adipose-specific FFA2 KO (AdFFA2-KO) mice to explore adipose-determined outcomes when mice are fed obesogenic challenge diets with or without fiber-induced production of SCFAs for receptor activation. After confirming that Adiponectin-Cre x FFA2 fl/fl mice have no congenital defects and are metabolically similar to FFA2 fl/fl control mice on a normal chow diet, mice were placed on either a high fat, high sugar Western Diet (WD) or on WD supplemented with 10% fructooligosaccharides – a fermentable dietary fiber. On WD, AdFFA2-KO mice had significantly decreased glucose tolerance compared to floxed controls with no other clearly observable effects on basic metabolic parameters. Interestingly, upon receptor activation with a fiber-supplemented diet, AdFFA2-KO mice were moderately protected from WD-induced weight gain. Our ongoing research aims to detangle the observed phenotypic differences and demystify the FFA2-adipose signaling cascade using a multifaceted approach including in vivo assessment of food intake and energy expenditure, ex vivo evaluation of lipolysis and fatty-acid uptake with FFA2 agonists and antagonists, as well as RTqPCR probing of adipose-derived cytokines (adipokines) with known roles in the weight gain-weight loss cycle. Presentation: Friday, June 16, 2023