Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight gain, hyperlipidemia, and hepatic steatosis in db/db mice.
OBJECTIVE
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.


CONCLUSIONS
DGAT1 may be an effective therapeutic target for the treatment of obesity, hyperlipidemia and hepatic steatosis.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Xiao-dong
XD
Zhang
Jian-wei
JW
Yan
Gui-rui
GR
Yan
Xiao-yun
XY
Sun
Jun
J
Ji
Yi-ming
YM
Li
You-hong
YH
Hu
He-yao
HY
Wang
D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054411:Receptors, Leptin / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood; D015430:Weight Gain / Q000187:drug effects*
D001713:Biphenyl Compounds; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005227:Fatty Acids; C555346:H128 compound; D010671:Phenylurea Compounds; D054411:Receptors, Leptin; D014280:Triglycerides; C515447:leptin receptor, mouse; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase