(OR17-01-24) Adipocyte-Specific Deletion of Free Fatty Acid Receptor 2 (FFAR2) Worsens Energy Metabolism in Diet-Induced Obese Mice

Objectives: The short-chain fatty acid (SCFA) acetate, produced by gut microbes, beneficially impacts host metabolism. Because acetate binds free-fatty acid receptor 2 (FFAR2), which is highly expressed on adipocytes, we hypothesized that increasing systemic acetate improves adipose tissue function and prevents obesity-related disorders via adipocyte FFAR2.

Methods: To test this hypothesis, male C57BL/6J (wild-type, WT) and adipocyte FFAR2-deficient (Ad-FFAR2 KO) mice were fed a high fat high sucrose (HFHS) diet for 8 weeks, followed by 5 weeks of oral supplementation with acetate (200 mM in drinking water) or dietary fiber (10% w/w chicory root inulin admixed into HFHS diet), known strategies to increase gut acetate. Energy balance (body weight and composition) and metabolic parameters (glucose and insulin tolerance) were assessed.

Results: HFHS-fed Ad-FFAR2 KO mice exhibited increased body weight (5.3%) and worse glucose metabolism compared to WT mice. While the addition of acetate in HFHS-fed WT mice increased body weight gain and body adiposity, there was no effect on glucose metabolism. Conversely, in Ad-FFAR2 KO mice, acetate did not impact body weight, but improved glucose tolerance. In contrast, WT HFHS-fed mice supplemented with inulin had less body weight gain, and adiposity, accompanied by improvements in glucose homeostasis, effects that were not observed in Ad-FFAR2 KO mice.

Conclusions: Our findings suggest that FFAR2 signaling in adipocytes is required for regulation of body weight and glucose metabolism. Systemic acetate improved glucose tolerance independently from Ad-FFAR2. Supplementing an obesogenic diet with inulin reduced body weight and adiposity and improved glucose homeostasis in WT mice, but not in Ad-FFAR2 KO mice. This indicates that limiting SCFA signaling to adipose tissue is metabolically detrimental. Strategies to perturb gut microbiota could be used to treat obesity and its complications.

Funding Sources: National Institute of Diabetes and Digestive and Kidney Diseases (P30); National Institutes of Health training programs in Diabetes, Obesity, and Metabolism (T32), Obesity and Nutrition, Obesity, and Atherosclerosis (T32); United States Department of Agriculture National Institute of Food and Agriculture (R01)