Intestinal FFA2 and FFA3 Mediate Obesogenic Effects in Mice on a Western Diet

Free fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3) are two highly similar G protein-coupled receptors belonging to the free fatty acid receptor family. Their ligands are short-chain fatty acids (SCFAs), which are produced by the gut microbiome and play diverse roles in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA2 and FFA3 are broadly expressed in a multitude of tissues including the intestine, pancreas, adipose and central nervous system, where they contribute to metabolic homeostasis via a summation of their tissue specific effects. FFA2 and FFA3 are highly expressed within the intestinal epithelium – the major site of SCFA generation – and have been identified in hormone-secreting enteroendocrine cells as well as intestinal epithelial cells. However, due conflicting data, the respective roles of FFA2 and FFA3 within the intestine and their effects on physiology and metabolism are still largely unclear. Previous in vivo studies involving these receptors have largely relied on global knockout mouse models, making it difficult to characterize their intestine-specific effects. To overcome this challenge, we generated novel intestine-specific knockout mouse models for FFA2 and FFA3 individually and report the first in vivo characterization of each receptor in the intestine while revealing novel insights into their functions. Following model validation, we conducted a general metabolic assessment of male Villin-Cre FFA2 (Vil-FFA2) and Villin-Cre-FFA3 (Vil-FFA3) mice on standard chow diet and observed no congenital or time-dependent defects. Because dietary changes are known to alter the composition of the gut microbiome, and thereby SCFA production, a long-term obesogenic challenge was performed on male Vil-FFA2 and Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high fat, high-sugar “Western diet.” Mice were placed on either a low-fat control diet (CD) or Western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. We found that both Vil-FFA2 and Vil FFA3 mouse strains were largely protected from diet-induced obesity and developed significantly less fat mass as well as reduced adipocyte hypertrophy in both subcutaneous and visceral adipose tissues. iii In the WD-fed Vil-FFA2 group, these effects were partially driven by a significant reduction in food intake. Collectively, these findings indicate a novel role of intestinal FFA2 and FFA3 in mediating the metabolic consequences of a Western diet. Moreover, these data support an intestine-specific role of FFA2 and FFA3 in whole-body metabolic homeostasis and in the development of obesity.