The free fatty acid receptor 1 (FFA1/GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have been widely considered as promising targets for type 2 diabetes mellitus (T2DM) due to their respective roles in promoting insulin secretion and improving insulin sensitivity. Hence, the dual FFA1/PPARδ agonists may exert synergistic effects by simultaneously activating FFA1 and PPARδ. The present study performed systematic exploration around previously reported FFA1 agonist 2-(2-fluoro-4-((2'-methyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)acetic acid (lead compound), leading to the identification of a novel dual FFA1/PPARδ agonist 2-(2-fluoro-4-((3-(6-methoxynaphthalen-2-yl)benzyl)oxy)phenoxy)acetic acid (the optimal compound), which displayed high selectivity over PPARα and PPARγ. In addition, the docking study provided us with detailed binding modes of the optimal compound in FFA1 and PPARδ. Furthermore, the optimal compound exhibited greater glucose-lowering effects than lead compound, which might attribute to its synergistic effects by simultaneously modulating insulin secretion and resistance. Moreover, the optimal compound has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg Therefore, our results provided a novel dual FFA1/PPARδ agonist with excellent glucose-lowering effects in vivo.

01 Dec 2020·Journal of Animal Science and BiotechnologyQ1 · AGRICULTURAL & FORESTRY SCIENCE

Effects of maternal dietary omega-3 polyunsaturated fatty acids and methionine during late gestation on fetal growth, DNA methylation, and mRNA relative expression of genes associated with the inflammatory response, lipid metabolism and DNA methylation in placenta and offspring’s liver in sheep

Q1 · AGRICULTURAL & FORESTRY SCIENCE

ArticleOA

Author: Rosa Velazquez, Milca ; Pinos Rodriguez, Juan Manuel ; Batistel, Fernanda ; Relling, Alejandro Enrique

AbstractBackgroundOmega-3 PUFA or methionine (Met) supply during gestation alters offspring physiology. However, the effect of both nutrients on fetal development has not been explored. Our objective was to determine the effects of supplementation of these two nutrients during late gestation on fetal growth, DNA methylation, and mRNA expression of genes associated with the inflammatory response, and DNA methylation. Ewes (n = 5/treatment) were fed from day 100 to 145 of gestation one of the following treatments: 1) basal diet (NS) without fatty acids (FS) or methionine (MS) supplementation; 2) FS (10 g/kg Ca salts, source omega-3 PUFA); 3) MS (1 g/kg rumen protected methionine); and 4) FS and MS (FS-MS). On day 145, ewes were euthanized, and data from dams and fetus was recorded. Placenta (cotyledon), fetal liver, and blood samples were collected.ResultsA treatments interaction on fetal liver weight, ewe body weight and body condition score (BCS) was observed; FS-MS were heavier (P < 0.01) than FS and MS, and FS-MS ewes had a better (P = 0.02) BCS than NS. Methionine increased (P = 0.03) ewe plasma glucose concentration. Fetal liver global DNA methylation increased (P < 0.01) in FS and MS. Dietary treatments modify the mRNA relative expression on some of the genes evaluated. In the fetal liver, FS increased (P = 0.04) the mRNA relative expression of arachidonate-5-lipoxygenase-activating-protein and tended to decrease (P = 0.06) methionine-adenosyltransferase-1A. Moreover, MS decreased (P = 0.04) DNA-methyltransferase-1 and tended to decrease (P = 0.08) free-fatty-acid-receptor-1 mRNA relative expression. Furthermore, FS-MS decreased mRNA relative expression of tumor-necrosis-factor-alpha (P = 0.05), peroxisome-proliferator-activated-receptor-delta (P = 0.03) and gamma (P = 0.04), tended to decrease (P ≤ 0.09) interleukin-6, fatty-acid-transport-protein-1, and delta-5-desaturase, and increased adenosylhomocysteinase (P = 0.04) mRNA relative expression. In cotyledon, FS tended to decrease fatty acid binding protein 4 (P = 0.09) mRNA relative expression.ConclusionOmega-3 PUFA and Met supplementation improves dam’s performance in late gestation, which was positively correlated with an increase in offspring’s liver development. Moreover, FS-MS decreased mRNA relative expression of proinflammatory cytokines, and lipogenic genes, and increased the expression on an enzyme that has an important role in methylation.

01 Nov 2020·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

HWL-088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis

Q3 · MEDICINE

Article

Author: Hu, Lijun ; Wang, Guangji ; Zhou, Zongtao ; Ren, Qiang ; Li, Zheng ; Deng, Liming ; Wang, Bin ; Cai, Zongyu

AbstractObjectivesNonalcoholic fatty liver (NAFLD), a chronic progressive liver disease, is highly correlated with pathoglycemia, dyslipidemia and oxidative stress. The free fatty acid receptor 1 (FFA1) agonists have been reported to improve liver steatosis and fibrosis, and the peroxisome proliferator-activated receptor δ (PPARδ) plays a synergistic role with FFA1 in energy metabolism and fibrosis. HWL-088, a PPARδ/FFA1 dual agonist, exerts better glucose-lowering effects than the representative FFA1 agonist TAK-875. However, the ability of HWL-088 to protect NAFLD was unknown. This study aimed to discover a new strategy for the treatment of NAFLD.MethodsThe methionine- and choline-deficient diet (MCD)-induced Nonalcoholic steatohepatitis (NASH) model was constructed to evaluate the effects of HWL-088.Key findingsAdministration of HWL-088 exerted multiple benefits on glucose control, lipid metabolism and fatty liver. Further mechanism research indicated that HWL-088 promotes lipid metabolism by decreasing lipogenesis and increasing lipolysis. Moreover, HWL-088 attenuates NASH by regulating the expression levels of genes related to inflammation, fibrosis and oxidative stress.ConclusionsThese positive results indicated that PPARδ/FFA1 dual agonist HWL-088 might be a potential candidate to improve multiple pathogenesis of NASH.

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