Merck Research Laboratories, Rahway, New Jersey, USA.
PLoS One. 2013;8(1):e54480. doi: 10.1371/journal.pone.0054480. Epub 2013 Jan 15.
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.
二酰基甘油酰基转移酶-1（DGAT1）是治疗肥胖症和相关代谢性疾病的潜在治疗靶点。然而，用于代谢益处的 DGAT1 抑制程度尚不清楚。在这里，我们发现小鼠的部分 DGAT1 缺乏可抑制餐后甘油三酯血症，仅在进食高脂质含量的餐后才会升高胰高血糖素样肽-1（GLP-1）和肽 YY（PYY），并且不能预防饮食引起的肥胖。最大程度的 DGAT1 抑制可导致在进食具有生理相关脂质含量的餐后，GLP-1 和 PYY 的分泌增强。最后，将 DGAT1 抑制与二肽基肽酶-4（DPP-4）抑制相结合，可进一步增强小鼠和犬体内的活性 GLP-1。本研究表明，靶向 DGAT1 以增强餐后肠道激素分泌需要最大程度的抑制，并提示与 DPP-4i 联合使用可能是开发用于治疗代谢性疾病的 DGAT1 抑制剂的一种策略。
