Essential Role for Protein Kinase Cζ in Oleic Acid-Induced Glucagon-Like Peptide-1 Secretion in Vivo in the Rat

• Published in: Endocrinology (Philadelphia) Vol. 152; no. 4; pp. 1244 - 1252
• Main Authors: Iakoubov, Roman, Ahmed, Ausma, Lauffer, Lina M., Bazinet, Richard P., Brubaker, Patricia L.
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Oxford University Press 01.04.2011; Endocrine Society
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; Colon - drug effects; Colon - metabolism; Diabetes mellitus (non-insulin dependent); Fatty acids; Fundamental and applied biological sciences. Psychology; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - blood; Glucagon-Like Peptide 1 - secretion; Ileum; Ileum - drug effects; Ileum - metabolism; In vivo methods and tests; Ingestion; Kinases; L cells; Mice; Oleic acid; Oleic Acid - pharmacology; Oral administration; Peptides; Physiological effects; Protein kinase C; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein transport; Proteins; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - genetics; RNA, Small Interfering - physiology; siRNA; Therapeutic targets; Vertebrates: endocrinology; Rat; Enzyme; Secretion; Transferases; Non-specific serine/threonine protein kinase; Rodentia; Monounsaturated fatty acid; Lipids; Glucagon like peptide 1; In vivo; Vertebrata; Gastrointestinal hormone; Mammalia; Oleic acid; Animal
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2010-1352

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.