Inhibition of MGAT2 modulates fat‐induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high‐fat diet

Abstract

Monoacylglycerol O‐acyltransferase 2 (MGAT2) is one of the key enzymes responsible for triglyceride (TG) re‐synthesis in the small intestine. We have previously demonstrated that pharmacological inhibition of MGAT2 has beneficial effects on obesity and metabolic disorders in mice. Here, we further investigate the effects of MGAT2 inhibition on (a) fat‐induced gut peptide release and fat intake in normal mice and (b) metabolic disorders in high‐fat diet (HFD)‐fed ob/ob mice, a model of severe obesity and type 2 diabetes mellitus, using an orally bioavailable MGAT2 inhibitor Compound B (CpdB). CpdB inhibited elevation of plasma TG in mice challenged with an oil‐supplemented liquid meal. Oil challenge stimulated the secretion of two gut anorectic hormones (peptide tyrosine–tyrosine and glucagon‐like peptide‐1) into the bloodstream, and these responses were augmented in mice pretreated with CpdB. In a two‐choice test using an HFD and a low‐fat diet, CpdB selectively inhibited intake of the HFD in normal mice. Administration of CpdB to HFD‐fed ob/ob mice for 5 weeks suppressed food intake and body weight gain and inhibited elevation of glycated hemoglobin. These results indicate that pharmacological MGAT2 inhibition modulates fat‐induced gut peptide release and fat intake in normal mice and improves obesity and diabetes in HFD‐fed ob/ob mice and thus may have potential for development into a treatment of obesity and its related metabolic diseases.

Involvement of the vagus nerve in the anorectic effect of monoacylglycerol acyltransferase 2 inhibition in mice

“…Moreover, MGAT2 inhibition upregulated the expression of c-fos in the NTS, which receives afferent input from the vagus nerve, and increased the jejunal OEA level after HFD re-feeding. Following lipid gavage, MGAT2 inhibition elevated the plasma levels of PYY and total GLP-1, which is in agreement with previous study findings, 8,13,27,28 and increased the jejunal and ileal levels of OEA. These appetite regulators inhibit feeding behavior through the afferent vagus nerve.…”

Effects of Dietary Fiber Sources during Gestation on Stress Status, Abnormal Behaviors and Reproductive Performance of Sows

“…Before feeding and at 2 h after feeding on day 70 of gestation, and before feeding on day 109 of gestation, blood samples were collected into vacuum tubes (5 mL) and labeled heparinized tubes (5 mL) from 24 sows (eight sows per dietary treatment) by ear vein puncture with a minimum amount of stress. Collection tubes for blood samples of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) contained a mixture of inhibitors (dipeptidyl peptidase-4 inhibitor (10 µL/mL blood), aprotinin (50 µL/mL blood) and Pefabloc SC (50 µL/mL blood]) to prevent degradation of the peptides [20,21]. Samples for serum assays (tubes containing no anticoagulant) were stored at room temperature for 4 h and then centrifuged for 5 min at 5000 ×g at 4 • C to collect the serum, followed by storage in labeled microfuge tubes at −80 • C until further analysis.…”

“…The same 8 sows per group were used to analyze GLP-1, PYY, and cortisol on day 70 of gestation. Before analysis of GLP-1 and PYY, serum was thawed, and an additional protease inhibitor cocktail was added according to published method [20]. The concentrations of GLP-1 and PYY in serum were analyzed using an ultrasensitive pig GLP-1 and PYY enzyme-linked immunosorbent assay (ELISA) kit (CUSABIO, Wuhan, Hubei, China) according to the operation instructions.…”

The Identification of Key Genes and Biological Pathways in Polycystic Ovary Syndrome and its Complications by Next Generation Squancing (NGS) and Bioinformatics Analysis

“…This study indicated that enriched genes might play important role in PCOS. As previously reported, FOXP3 [446], TIMP4 [447], OAS3 [448], SOCS1 [128], CD74 [129], PLK1 [449], TGFB1 [450], RAPGEF1 [451], SERPINH1 [452], ATF5 [66], GATA6 [133], IGF2BP1 [453], IRX3 [454], FOXC2 [455], SNHG17 [456], TAF1C [457], HHIP (hedgehog interacting protein) [458], POMC (proopiomelanocortin) [459], DOK5 [76], COL1A1 [460], POSTN (periostin) [461], SOD3 [462], ADAMTS13 [463], FABP5 [464], MAPK11 [465], KCTD15 [83], HSPG2 [466], MST1 [467], MGAT2 [468], LGR5 [469], SPINK1 [470], CYP19A1 [471], PLAC8 [90], CD36 [472], AQP5 [473], GIPR (gastric inhibitory polypeptide receptor) [474], ARG1 [475], SORL1 [476], CD4 [477], F11R [478], LEPR (leptin receptor) [479], CDH13 [480], AR (androgen receptor) [481], FOXO1 [102], MALT1 [482], PAM (peptidylglycine alpha-amidating monooxygenase) [483], B2M [484], TCF4 [485], CAV2 [486], HSBP1 [487], COLEC12 [488], ADRA2A [489], SLC38A4 [490], TM6SF2 [491], GLP2R [111], KLB (klotho beta) [492], NFAT5 [493], PON2 [494], ZMAT3 [495], DST (dystonin) [426], MGST3 [496], COQ2 [118], EPHX2 [497], C2 [181] and FAM3C [120] are altered expression in type 2 diabetes mellitus. Previous studies have shown that DRD4 [498], TIMP4 [499], SOCS1 [500], CD74 [501], TGFB1 [502], ACTG2 [503], ISG15 [504], HOXC8 [...…”