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

Abstract

( 1, 2 ). 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 ).In the small intestine dietary TAGs are hydrolyzed to 2-monoacylglycerols (MAGs) and fatty acids (FAs) that are absorbed . Specifi c binding proteins in the enterocytes shuttle MAG and FFA to the endoplasmic reticulum for reesterifi cation. 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 ). This MAG pathway is important after eating, when intestinal MAG levels are high ( 5 ). DGAT-1 is one of two known DGAT enzymes ( 6 ) in tissues associated with TAG synthesis, including the small intestine ( 6, 7 ), where DGAT-1 is involved in fat absorption, lipoprotein assembly, and regulation of plasma TAG concentrations ( 7 ). DGAT-1 knockout (dgat-1 Obesity is a global epidemic and a major risk factor for type 2 diabetes, hypertension, cardiovascular disease, and other ailments. The development of obesity is multifactorial 28 February 2013. Published, JLR Papers in Press, February 28, 2013 DOI 10.1194 Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats Abbreviations: AMPK ␣ , AMP-activated protein kinase-␣ ; ASP, acid soluble products; AUC, area under the curve; BHB, ␤ -hydroxybutyrate; BT, body temperature; BW, body weight; CFA, conditioned fl avor avoidance; CPT-1, carnitine palmitoyltransferase-1; DAG, sn -1,2-diacylglycerol; DGAT-1, acyl-CoA:diacylglycerol acyltransferase-1; DGAT-1i, diacylglycerol acyltransferase-1 inhibitor; dgat-1 Ϫ / Ϫ This work was supported by Swiss National Science Foundation Grant 31_130665 (W.L.). Manuscript received 19 December 2012 and in revised form

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