title: Diacylglycerol acyltransferase-1 (DGAT1) inhibition perturbs postprandial gut hormone release.
abstract: Diacylglycerol acyltransferase-1 (DGAT1) is a potential therapeutic target for treatment of obesity and related metabolic diseases. However, the degree of DGAT1 inhibition required for metabolic benefits is unclear. Here we show that partial DGAT1 deficiency in mice suppressed postprandial triglyceridemia, led to elevations in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) only following meals with very high lipid content, and did not protect from diet-induced obesity. Maximal DGAT1 inhibition led to enhanced GLP-1 and PYY secretion following meals with physiologically relevant lipid content. Finally, combination of DGAT1 inhibition with dipeptidyl-peptidase-4 (DPP-4) inhibition led to further enhancements in active GLP-1 in mice and dogs. The current study suggests that targeting DGAT1 to enhance postprandial gut hormone secretion requires maximal inhibition, and suggests combination with DPP-4i as a potential strategy to develop DGAT1 inhibitors for treatment of metabolic diseases.
authors: Merck Research Laboratories, Rahway, New Jersey, USA.
authors: Hua V
authors: HV
authors: Lin
authors: Dunlu
authors: D
authors: Chen
authors: Zhu
authors: Z
authors: Shen
authors: Lei
authors: L
authors: Zhu
authors: Xuesong
authors: X
authors: Ouyang
authors: Aurawan
authors: A
authors: Vongs
authors: Yanqing
authors: Y
authors: Kan
authors: John M
authors: JM
authors: Levorse
authors: Edward J
authors: EJ
authors: Kowalik
authors: Daphne M
authors: DM
authors: Szeto
authors: Xiaorui
authors: X
authors: Yao
authors: Jianying
authors: J
authors: Xiao
authors: Shirley
authors: S
authors: Chen
authors: Jinqi
authors: J
authors: Liu
authors: Marga
authors: M
authors: Garcia-Calvo
authors: Myung K
authors: MK
authors: Shin
authors: Shirly
authors: S
authors: Pinto
mesh_terms: D000818:Animals; D001483:Base Sequence; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004032:Diet; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D005260:Female; D005746:Gastric Emptying / Q000235:genetics; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D018628:Gene Dosage; D005786:Gene Expression Regulation; D023061:Gene Order; D005838:Genotype; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D019518:Postprandial Period; D014280:Triglycerides / Q000097:blood
chemical_list: D005768:Gastrointestinal Hormones; D014280:Triglycerides; D052216:Glucagon-Like Peptide 1; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D018819:Dipeptidyl Peptidase 4