TY - JOUR

T1 - The impact of short chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon

AU - Christiansen, Charlotte Bayer

AU - Gabe, Maria Buur Nordskov

AU - Svendsen, Berit

AU - Dragsted, Lars Ove

AU - Rosenkilde, Mette

AU - Holst, Jens Juul

N1 - CURIS 2018 NEXS 262

PY - 2018

Y1 - 2018

N2 - The colonic epithelium harbors a large number of endocrine cells, but little is known about the endocrine functions of the colon. However, the high density of GLP-1 and PYY secreting L-cells is of great interest because of the potential anti-diabetic and anti-obesity effects of GLP-1 and PYY. Short chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L-cells. We used the isolated perfused rat colon as a model of colonic endocrine secretion and studied the effects of the predominant SCFAs formed: acetate, propionate and butyrate. We show that luminal and especially vascular infusion of acetate and butyrate significantly increases colonic GLP-1 secretion, and to a minor extent also PYY secretion, but only after enhancement of intracellular cAMP. Propionate neither affected GLP-1 nor PYY secretion whether administered luminally or vascularly. A FFAR2 and FFAR3 specific agonist (CFMB/AR420626) had no effect on colonic GLP-1 output, and a FFAR3 antagonist (AR399519) did not decrease the SCFA-induced GLP-1 response. However, the voltage-gated Ca2+-channel blocker nifedipine, the KATP-channel opener diazoxide and the ATP synthesis inhibitor 2,4-dinitrophenol completely abolished the responses. FFAR2 receptor studies confirmed low-potent partial agonism of acetate, propionate and butyrate, compared to CFMB which is a full agonist with around 750-fold higher potency than the SCFAs. In conclusion, SCFAs may increase colonic GLP-1/PYY secretion, but FFAR2/FFAR3 do not seem to be involved. Rather, SCFAs are metabolized and appear to function as a colonocyte energy source.

AB - The colonic epithelium harbors a large number of endocrine cells, but little is known about the endocrine functions of the colon. However, the high density of GLP-1 and PYY secreting L-cells is of great interest because of the potential anti-diabetic and anti-obesity effects of GLP-1 and PYY. Short chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L-cells. We used the isolated perfused rat colon as a model of colonic endocrine secretion and studied the effects of the predominant SCFAs formed: acetate, propionate and butyrate. We show that luminal and especially vascular infusion of acetate and butyrate significantly increases colonic GLP-1 secretion, and to a minor extent also PYY secretion, but only after enhancement of intracellular cAMP. Propionate neither affected GLP-1 nor PYY secretion whether administered luminally or vascularly. A FFAR2 and FFAR3 specific agonist (CFMB/AR420626) had no effect on colonic GLP-1 output, and a FFAR3 antagonist (AR399519) did not decrease the SCFA-induced GLP-1 response. However, the voltage-gated Ca2+-channel blocker nifedipine, the KATP-channel opener diazoxide and the ATP synthesis inhibitor 2,4-dinitrophenol completely abolished the responses. FFAR2 receptor studies confirmed low-potent partial agonism of acetate, propionate and butyrate, compared to CFMB which is a full agonist with around 750-fold higher potency than the SCFAs. In conclusion, SCFAs may increase colonic GLP-1/PYY secretion, but FFAR2/FFAR3 do not seem to be involved. Rather, SCFAs are metabolized and appear to function as a colonocyte energy source.

KW - Faculty of Science

KW - Colon

KW - GLP-1

KW - GPCRs

KW - PYY

KW - Short chain fatty acids

U2 - 10.1152/ajpgi.00346.2017

DO - 10.1152/ajpgi.00346.2017

M3 - Journal article

C2 - 29494208

VL - 315

SP - G53-G65

JO - American Journal of Physiology: Gastrointestinal and Liver Physiology

JF - American Journal of Physiology: Gastrointestinal and Liver Physiology

SN - 0193-1857

IS - 1

ER -