Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance.
The effect of peptide tyrosine-tyrosine (PYY) on feeding is well established but currently its role in glucose homeostasis is poorly defined. Here we show in mice, that intraperitoneal (ip) injection of PYY3-36 or Y2R agonist improves nutrient-stimulated glucose tolerance and enhances insulin secretion; an effect blocked by peripheral, but not central, Y2R antagonist administration. Studies on isolated mouse islets revealed no direct effect of PYY3-36 on insulin secretion. Bariatric surgery in mice, enterogastric anastomosis (EGA), improved glucose tolerance in wild-type mice and increased circulating PYY and active GLP-1. In contrast, in Pyy-null mice, post-operative glucose tolerance and active GLP-1 levels were similar in EGA and sham-operated groups. PYY3-36 ip increased hepato-portal active GLP-1 plasma levels, an effect blocked by ip Y2R antagonist. Collectively, these data suggest that PYY3-36 therefore acting via peripheral Y2R increases hepato-portal active GLP-1 plasma levels and improves nutrient-stimulated glucose tolerance.
Centre for Obesity Research, Department of Medicine, University College London, Rayne Institute, 5 University Street, WC1E 6JJ, London, UK.
Keval
K
Chandarana
Cigdem
C
Gelegen
Elaine E
EE
Irvine
Agharul I
AI
Choudhury
Chloé
C
Amouyal
Fabrizio
F
Andreelli
Dominic J
DJ
Withers
Rachel L
RL
Batterham
AUC, area under the curve; CNS, central nervous system; DPP-4, di-peptidyl peptidase-4; EGA, entero-gastric anastomosis; GLP-1; Glucose homeostasis; HFD, high-fat diet; ICV, intracerebroventricular; IPGTT, intraperitoneal glucose tolerance test; PYY; PYY, peptide tyrosine–tyrosine; T2DM, type 2 diabetes mellitus; WT, wild-type; Y2-receptor; Y2R, Y2-receptor; aCSF, artificial cerebrospinal fluid; active GLP-1, glucagon-like peptide-1(7-36)amide; ip, intraperitoneal