title: Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats.
abstract: Acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final step in triacylglycerol (TAG) synthesis and is highly expressed in the small intestine. Because DGAT-1 knockout mice are resistant to diet-induced obesity, we investigated the acute effects of intragastric (IG) infusion of a small molecule diacylglycerol acyltransferase-1 inhibitor (DGAT-1i) on eating, circulating fat metabolites, indirect calorimetry, and hepatic and intestinal expression of key fat catabolism enzymes in male rats adapted to an 8 h feeding-16 h deprivation schedule. Also, the DGAT-1i effect on fatty acid oxidation (FAO) was investigated in enterocyte cell culture models. IG DGAT-1i infusions reduced energy intake compared with vehicle in high-fat diet (HFD)-fed rats, but scarcely in chow-fed rats. IG DGAT-1i also blunted the postprandial increase in serum TAG and increased β-hydroxybutyrate levels only in HFD-fed rats, in which it lowered the respiratory quotient and increased intestinal, but not hepatic, protein levels of Complex III of the mitochondrial respiratory chain and of mitochondrial hydroxymethylglutaryl-CoA synthase. Finally, the DGAT-1i enhanced FAO in CaCo2 (EC50 = 0.3494) and HuTu80 (EC50 = 0.00762) cells. Thus, pharmacological DGAT-1 inhibition leads to an increase in intestinal FAO and ketogenesis when dietary fat is available. This may contribute to the observed eating-inhibitory effect.
authors: Physiology and Behavior Laboratory, Institute of Food, Nutrition, and Health, Swiss Federal Institute of Technology, Zurich, Switzerland. gudrun-schober@ethz.ch
authors: Gudrun
authors: G
authors: Schober
authors: Myrtha
authors: M
authors: Arnold
authors: Susan
authors: S
authors: Birtles
authors: Linda K
authors: LK
authors: Buckett
authors: Gustavo
authors: G
authors: Pacheco-López
authors: Andrew V
authors: AV
authors: Turnbull
authors: Wolfgang
authors: W
authors: Langhans
authors: Abdelhak
authors: A
authors: Mansouri
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059305:Diet, High-Fat; D014450:Electron Transport Complex III / Q000378:metabolism; D002149:Energy Intake; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase; D014450:Electron Transport Complex III