Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats

Gudrun Schober, Myrtha Arnold, Susan Birtles, Linda K. Buckett, Gustavo Pacheco-López, Andrew V. Turnbull, Wolfgang Langhans, Abdelhak Mansouri

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

AcylCoA: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 (EC 50 = 0.3494) and HuTu80 (EC 50 = 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 eatinginhibitory effect.

Original languageEnglish
Pages (from-to)1369-1384
Number of pages16
JournalJournal of Lipid Research
Volume54
Issue number5
DOIs
Publication statusPublished - 1 May 2013
Externally publishedYes

Keywords

  • AcylCoA:diacylglycerol acyltransferase-1
  • Eating
  • Enterocytes
  • High fat diet
  • Ketogenesis
  • Small intestine
  • Triacylglycerol

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