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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 ?-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.

SUBMITTER: Schober G

PROVIDER: S-EPMC3622331 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Schober Gudrun G Arnold Myrtha M Birtles Susan S Buckett Linda K LK Pacheco-López Gustavo G Turnbull Andrew V AV Langhans Wolfgang W Mansouri Abdelhak A

Journal of lipid research 20130228 5

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 mal ...[more]

PMID: 23449193

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Project description:Weaning stress in pigs is associated with low feed intake and poor nutrient utilization. Cysteine is a sulfur amino acid with key roles in pig production, but how cysteine metabolism and requirements are affected by weaning stress should be better defined. The objective of this study was to determine the collective impact of weaning and feed restriction on tissue cysteine metabolism. Pigs were weaned at 21-d age without access to feed (W; 6.90 ± 0.81 kg; n = 9; reflecting acute nutritional stress) or were not weaned and remained with the sow (nonweaned [NW]; 6.81 ± 0.65 kg; n = 8). At euthanasia (23-d age), blood, bile, liver, jejunum, and ileum tissues were collected. Plasma, bile, and tissue amino acid and amino thiol concentrations were analyzed by HPLC. The activity of glutamate cysteine ligase (GCL) and glutathione synthetase (GSS), enzymes needed for glutathione (GSH) production, and cysteine dioxygenase 1 (CDO1) were determined with activity assays followed by HPLC analysis of reaction products. Plasma (271 vs. 192 ± 19 µmol/L; P < 0.001) and liver (417 vs. 298 ± 33 nmol/g; P < 0.05) Cys concentrations were increased in W compared to NW pigs. Despite greater plasma Cys, jejunum and ileum Cys content were not affected by weaning (P > 0.10), whereas γ-glutamylcysteine (γ-GlyCys), the immediate precursor of GSH, declined in both jejunum (14.3 vs. 9.7 ± 1.4 nmol/g; P < 0.01) and ileum (11.2 vs. 6.4 ± 0.8 nmol/g; P < 0.001) in W pigs. Glutathione content was lower in the jejunum (1,379 vs. 1,720 ± 70 nmol/g; P < 0.05) and ileum (1,497 vs. 1,740 ± 74 nmol/g; P < 0.05) in W pigs. In the jejunum, GCL activity tended to be greater (0.56 vs. 0.39 ± 0.07 nmol γ-GluCys • mg-1 • min-1; P < 0.10), whereas GSS activity tended to be lower (1.11 vs. 1.38 ± 0.10 nmol GSH • mg-1 • min-1; P < 0.10) in W compared to NW pigs. In the ileum, the activities of GCL and GSS were not affected by weaning (P > 0.10). Although liver CDO1 activity was not different between groups (P < 0.10), liver taurine was greater in W compared to NW pigs (5,115 vs. 2,336 ± 912 nmol/g; P = 0.001). Bile concentrations of Cys (1,203 vs. 279 ± 103 µmol/L; P < 0.001) and cysteinylglycine (203 vs. 117 ± 33 µmol/L; P < 0.10), the direct product of GSH degradation, were greater in W compared to NW pigs. Collectively, these results suggest that systemic Cys is not effectively utilized for gut GSH production in newly weaned pigs; instead, it is oxidized to taurine and eliminated in bile.

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

Publications

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

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