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

doi:10.1194/jlr.m035154

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.

Highlights

Acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final step in triacylglycerol (TAG) synthesis and is highly expressed in the small intestine
Intragastric infusion of 3 and 9 mg/kg body weight (BW) diacylglycerol acyltransferase-1 inhibitor (DGAT-1i) reduced energy intake compared with vehicle mainly in high-fat diet (HFD)-fed rats
We here report that inhibition of DGAT-1, one of two known DGAT enzymes that catalyzes the final step in TAG resynthesis [6, 7] with an orally bioavailable and selective small-molecule DGAT-1 inhibitor (Compound 2) [17], reduced energy intake in rats fed a HFD, but not in rats fed chow

Summary

Introduction

Acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final step in triacylglycerol (TAG) synthesis and is highly expressed in the small intestine. Often an overconsumption of energy-dense, fat-rich food leads to excessive triacylglycerol (TAG) accumulation in adipose and nonadipose tissue This can result in insulin resistance and nonalcoholic fatty liver disease, emphasizing the need for pharmacotherapeutic approaches that are effective when a high-fat diet (HFD) is consumed [3]. Specific binding proteins in the enterocytes shuttle MAG and FFA to the endoplasmic reticulum for reesterification This involves the acylation from MAG to sn-1,2-diacylglycerol (DAG) by MAG acyltransferase and the acylation from DAG to TAG catalyzed by acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) (EC 2.3.1.20), the rate-limiting step in TAG synthesis [4]. DGAT-1 knockout (dgat-1Ϫ/Ϫ) mice are resistant to diet-induced obesity

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Conclusion