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

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 C zeta (PKC zeta) 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 PKC zeta 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 mu mol/g. To evaluate the direct effects of OA on GLP-1 secretion, 125 mMOA 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 PKC zeta 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 PKC zeta is necessary for the effects of OA on GLP-1 secretion in vivo. PKC zeta may therefore serve as a novel therapeutic target to enhance GLP-1 levels in patients with type 2 diabetes. (Endocrinology 152: 1244-1252, 2011)