title: Essential role for protein kinase Cζ in oleic acid-induced glucagon-like peptide-1 secretion in vivo in the rat.
abstract: Luminal monounsaturated long-chain fatty acids [e.g. oleic acid (OA)] increase secretion of the incretin, glucagon-like peptide-1 (GLP-1) from the ileocolonic L cell. However, it is not known whether OA ingestion causes a sufficient increase in distal luminal concentrations to directly enhance GLP-1 secretion. Furthermore, we have demonstrated that protein kinase Cζ (PKCζ) is required for OA-induced GLP-1 secretion in vitro; however, the physiological relevance of this finding remains unknown. Therefore, we have determined luminal OA concentrations in OA-fed rats and examined the effects of direct OA stimulation on GLP-1 secretion using a novel model of intestinal-specific PKCζ knockdown. Murine GLUTag L cells express numerous fatty acid transport proteins and take up OA in a saturable manner. Oral administration of OA increased the ileal chyme content of OA by 140-fold over 60-120 min (P < 0.05-0.01), peaking at 105 ± 50 μmol/g. To evaluate the direct effects of OA on GLP-1 secretion, 125 mm OA was rectally infused into the colon and terminal ileum of rats. Plasma bioactive GLP-1 increased from 20 ± 6 to 102 ± 21 pg/ml at 60 min (P < 0.01). However, pretreatment with ileocolonic adenoviral PKCζ small interfering RNA resulted in a 68 ± 8% reduction in the GLP-1 response to rectal OA (P < 0.001). The results of these studies indicate that OA levels in the rat terminal gut after oral ingestion are sufficient to induce GLP-1 secretion and that PKCζ is necessary for the effects of OA on GLP-1 secretion in vivo. PKCζ may therefore serve as a novel therapeutic target to enhance GLP-1 levels in patients with type 2 diabetes.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Roman
authors.initials: R
authors.lastname: Iakoubov
authors.forename: Ausma
authors.initials: A
authors.lastname: Ahmed
authors.forename: Lina M
authors.initials: LM
authors.lastname: Lauffer
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bazinet
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019301:Oleic Acid / Q000494:pharmacology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099221:Protein Kinase C zeta
chemical_list: D052216:Glucagon-Like Peptide 1; D019301:Oleic Acid; D011493:Protein Kinase C; D034741:RNA, Small Interfering; D000099221:Protein Kinase C zeta