Aim: To test whether pharmacological inhibition of Diacylglycerol acyltransferase 1 (DGAT1) by a small-molecule inhibitor H128 can improve metabolism disorders in leptin receptor-deficient db/db mice. Methods: To investigate the effect of H128 on intestinal fat absorption, db/db mice were acutely given a bolus of corn oil by gavage. The mice were further orally administered H128 (3 and 10 mg/kg) for 5 weeks. Blood glucose, lipids, insulin, ALT, and AST as well as hepatic triglycerides were measured. The insulin tolerance test was performed to evaluate insulin sensitivity. The expression of genes involved in fatty acid oxidation was detected by RT-PCR. Results: Oral administration of H128 (10 mg/kg) acutely inhibited intestinal fat absorption following a lipid challenge in db/db mice. Chronic treatment with H128 significantly inhibited body weight gain, decreased food intake, and induced a pronounced reduction of serum triglycerides. In addition, H128 treatment markedly ameliorated hepatic steatosis, characterized by decreased liver weight, lipid droplets, and triglyceride content as well as serum ALT and AST levels. Furthermore, H128 treatment increased the expression of the CPT1 and PPARα genes in liver, suggesting that H128 enhanced fatty acid oxidation in db/db mice. However, neither blood glucose nor insulin tolerance was affected by H128 treatment throughout the 5-week experimental period. Conclusion: DGAT1 may be an effective therapeutic target for the treatment of obesity, hyperlipidemia and hepatic steatosis.Keywords: diabetes; hepatic steatosis; obesity; hyperlipidemia; small-molecule inhibitor; H128; diacylglycerol acyltransferase 1; db/db mice; CPT1 gene; PPARα gene Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1470Sinica ( -1477 doi: 10.1038/aps.2010 Original Article * To whom correspondence should be addressed. Recent reports show that pharmacologic inhibition of DGAT1 by small molecules suppresses high-fat diet-induced body weight gain in diet-induced obese (DIO) mice [18,19] . However, to the best of our knowledge, no studies have examined the effects of small-molecule DGAT1 inhibitors on glucose metabolism in animal models. H128 ( Figure 1A) is a potent DGAT1 inhibitor with an IC 50 value of 98 nmol/L against human DGAT1 [19] . In this study, we sought to determine whether H128 could improve glucose metabolism in leptin receptor-deficient db/db mice, which spontaneously develop obesity and diabetes. We also evaluated the effects of H128 on body weight, blood lipids, and hepatic steatosis in db/db mice.
Materials and methodsCompound H128 was synthesized in the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. H128 was prepared in 0.5% Tween-80 solution in water for in vivo studies.
Animals and experimental protocolsMale C57BL/KsJ-Lep db (db/db) and their lean littermates, obtained from Jackson Laboratories (Bar Harbor, Maine, USA), were maintained in a 12:12 light-dark cycle with ad libitum access to water and a normal chow diet. The db/db mice at 10 weeks of age were divided in...
