Inhibition of Triglyceride Synthesis as a Treatment Strategy for Obesity

Abstract

Abstract-Because the ability to make triglycerides is essential for the accumulation of adipose tissue, inhibition of triglyceride synthesis may ameliorate obesity and its related medical consequences. Acyl coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of 2 DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 are resistant to obesity and have increased sensitivity to insulin and leptin. DGAT1-deficient mice are also resistant to diet-induced hepatic steatosis. The effects of DGAT1 deficiency on energy and glucose metabolism result in part from the altered secretion of adipocyte-derived factors. Although complete DGAT1 deficiency causes alopecia and impairs development of the mammary gland, these abnormalities are not observed in mice with partial DGAT1 deficiency. These findings suggest that pharmacological inhibition of DGAT1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes. O besity can be viewed as an energy balance disorder, arising when energy input exceeds energy output, with most of the excess calories converted into triglycerides and stored in the adipose tissue. Medications currently approved for the treatment of obesity attempt to restore energy balance primarily by decreasing energy input-by either suppressing appetite or interfering with lipid absorption in the small intestine. Because of the rapid increase in the prevalence of obesity worldwide and the lack of efficacy of current medical therapies, 1 efforts to develop novel pharmacological therapies for obesity have intensified.One potential therapeutic strategy involves inhibiting triglyceride synthesis. Although triglycerides are essential for normal physiology, excess triglyceride accumulation results in obesity and, particularly when it occurs in nonadipose tissues, is associated with insulin resistance. However, until recently it had been unclear whether disrupting triglyceride synthesis would be feasible or would instead cause significant adverse consequences. In the past several years, pharmacological inhibition of acyl coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) has emerged as a potential strategy for inhibiting triglyceride synthesis. Here, we review recent findings from studies of mice lacking DGAT1 that are pertinent to the prospects of DGAT1 as a pharmaceutical target. DGAT Enzymes and Triglyceride SynthesisThe cloning of genes encoding DGAT enzymes provided important molecular tools to examine the relationship between triglyceride synthesis and obesity. The DGAT1 gene was identified from its homology to acyl CoA:cholesterol acyltransferase genes 2,3 and was shown to encode an enzyme with DGAT activity. 2 The DGAT2 gene was identified byOriginal

Effects of Korean white ginseng extracts on obesity in high-fat diet-induced obese mice

“…DGAT1 is the enzyme which catalyzes the final step in the TG synthesis pathway and considered to play key regulatory role in TG synthesis (Chen and Farese 2000). DGAT1-deficient mice showed a reduced adipose mass in comparison to wild-type mice on a chow diet (Smith et al 2000;Chen and Farese 2005). As shown in Fig.…”

Triacylglycerol Metabolism In Adipose Tissue

“…Furthermore, in vitro studies have revealed that DGAT1, but not DGAT2, is a multifunctional acyltransferase able to catalyze the synthesis of DAG, retinyl esters and waxes, in addition to TAG [35]. The functional differences between these two enzymes are further emphasized by studies in mice lacking DGAT1 and 2 [34,[36][37][38][39]. While mice lacking DGAT2 have a drastic reduction in whole body TAG and die shortly after birth, mice lacking DGAT1 are viable, have improved insulin sensitivity, demonstrate modest reductions in tissue TAG and are resistant to diet-induced obesity.…”

Advances in adipose tissue metabolism

“…78 Inactivation of anabolic enzymes of fatty acid uptake and storage enhanced tissue glucose disposal or insulin secretion whereas disruptions in the catabolic process tended to impair insulin action or secretion. 79,80 Overexpression of DGAT1 in AT yields a mouse that is more obese but also more insulin sensitive. 81 In human AT, DGAT1 and fatty acid synthase expression are strongly correlated with insulin sensitivity.…”