Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms

Abstract

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.

MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus

“…Butyrate, the main energy source of the gut epithelium, seems to possess beneficial effect on insulin sensitivity and energy balance (26), whereas acetate and propionate mainly functions as substrates for gluconeogenesis and lipogenesis in the liver. Butyrate has been demonstrated to increase secretion of GLP1 and PYY from L-cells in the colon (26,27) and to change the intestinal transit time resulting in additional time for nutrient uptake by the host (28). The exact mechanisms by which SCFAs exert their effects are unclear, but they bind to G proteincoupled receptors (GPRs) GPR41 (FFAR3) and GPR43 (FFAR2), which are widely expressed in the intestinal mucosa, immune cells, liver, and adipose tissues (29).…”

Modulation of Gut Microbiota of Overweight Mice by Agavins and Their Association with Body Weight Loss

“…Agavins are fermented in both, cecum and colon, by saccharolytic microbiota producing short chain fatty acids (SCFA), mostly acetate, propionate and butyrate. SCFA are very important because they reduce body weight gain, through G-protein-coupled receptors (GPRs), influencing the secretion of hormones involved in appetite control [5][6][7]. In addition, SCFA increment through agavins fermentation in both, cecum and gut, induces a pH drop; which might change the intestinal microbiota structure [8,9].…”

Microbiota in Obesity

“…propionate, butyrate, acetate etc) signaling cascades are mediated by membrane surface G protein-coupled receptors (GPCRs), explicitly free fatty acid receptors 2 and 3 (FFAR2 and FFAR3). FFAR2 promotes +ve energy balance by stimulating adipogenesis, inhibiting lipolysis and decreasing expenditure of stored energy [14]. Its deficiency is associated with lower body fat mass, increased lean body mass, high energy expenditure, high core body temperature, increased insulin sensitivity, low triglyceride and hypocholesteroleamia [15].…”

“…Enteroendocrine cells express the SCFA receptor and this gives the gut microbiota the opportunity to regulate host metabolism by induction of gut hormones released by L-cells especially glucagon-like peptide (GLP) and peptide YY (PYY) in response to GPCRs activation [14]. These hormones control satiety by regulating the production and release of digestive enzymes [18].…”