HWL‐088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice

Abstract

Background and Purpose: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive antidiabetic target. This study characterizes the pharmacological profile of HWL-088(2-(2-fluoro-4-((2 0 -methyl-[1,1 0 -biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the longterm effects of HWL-088 alone and in combination with metformin in diabetic mice.Experimental Approach: In vitro effects of HWL-088 on FFAR1 and PPARα/γ/δ were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long-term effects on glucose and lipid metabolism were investigated in ob/ob mice.Key Results: HWL-088 is a highly potent FFAR1 agonist (EC 50 = 18.9 nM) with moderate PPARδ activity (EC 50 = 570.9 nM) and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK-875, and synergistic improvements were observed when combined with metformin. Moreover, HWL-088 and combination therapy improved β-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice.The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation.Abbreviations: ACC1, acetyl-CoA carboxylase 1; ALT, alanine aminotransferase; ANGPTL3, angiopoietin-like 3; Apo C-II, apolipoprotein C-II; Apo C-III, apolipoprotein C-III; AS160, TBC1 domain family member 4; AST, aspartate transaminase; ATGL, adipose triglyceride lipase; BAT, brown adipose tissue; CKMB, creatine kinase-MB; CPT1α, carnitine palmitoyl transferase 1α; FAS, fatty acid synthetase; FFAR1, free fatty acid receptor 1; FLIPR, fluorometric imaging plate reader; G6Pase, glucose-6-phosphatase; GLP-1, glucagon-like peptide 1; GLUT4, glucose transporter 4; GSK3β, glycogen synthase kinase 3β; HbA1c, glycosylated haemoglobin; IP3, inositol triphosphate; LCAD, long-chain specific acyl-CoA dehydrogenase; LPL, lipoprotein lipase; OGTT, oral glucose tolerance test; PCNA, proliferating cell nuclear antigen; PDase, pyruvate dehydrogenase; PDX-1, pancreas duodenum homeobox-1; PEPCK, phosphoenol pyruvate carboxykinase; RT-PCR, reverse transcription-PCR; SAR, structure-activity relationship; SCD1, stearoyl-CoA desaturase 1; SD rats, Sprague-Dawley rats; SREBP-1c, sterol regulatory element-binding protein 1c; T2DM, type 2 diabetes mellitus; WAT, white adipose tissue.

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

“…[ 10,11 ] In previous studies, we found HWL‐088 exerted stronger hypoglycemic effect than TAK‐875, the most advanced candidate of FFA1 agonists. [ 29 ] However, the ability of HWL‐088 to protect NAFLD was unknown. Herein, we first evaluated the effects of PPARδ/FFA1 dual agonist in NASH model.…”

“…[ 25–28 ] A comprehensive structure‐activity relationship study provided HWL‐088 (the structure is shown in Figure 1a), a PPARδ/FFA1 dual agonist. [ 29,30 ] Herein, the chronic effects of HWL‐088 were explored in the methionine‐ and choline‐deficient diet (MCD) diet‐fed db/db mice, a typical model of NASH. [ 31 ] HWL‐088 alleviated fatty liver by maintaining glucose stability, improving fat metabolism, liver fibrosis, inflammation and oxidative stress.…”

Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

“…Another mechanism of FFA uptake is by binding to the free fatty acid receptor 1, also known as the G protein-coupled receptor (GPR) 40 [ 70 ]. GPR40 activates phospholipase C (PLC) [ 71 ] which is degrading phosphatidylinositol-4,5-bisphosphate into the signaling molecules inositol trisphosphate (IP3) and diacylglycerol to increase the cytosolic calcium (Ca) concentration [ 72 ]. Furthermore, Ca storages of the mitochondria are released by PLC, and the endoplasmic reticulum (ER) can release its Ca storages through the activation of GPR40 [ 71 ].…”

“…The accumulation of especially long chain acyl-CoA in the cytosol induces functional impairment and apoptosis by mediating signaling effects and Ca release. Acyl-CoA interacts with PPARα [ 138 ] promoting apoptosis [ 72 ], uncoupling of respiratory complexes [ 133 ], and storage as TG [ 158 ], ultimately impairing GSIS [ 157 ]. Based on the acyl-CoA content of hamster islet transformed-tioguanine resistant clone 15 (HIT-T15) cells and the average distribution of cytosolic and mitochondrial mass in mouse pancreas [ 159 ], it is estimated that the cytosolic acyl-CoA concentration in rodent β-cells is 90 µM, while tissue concentrations are unknown [ 160 ].…”

“…The short time treatment with low FFA concentration led to the activation of PPARγ coactivator 1α/β [ 193 ] and a depletion of Ca storages by GPR40, mediating insulin release [ 170 ]. The so-called “fatty acid stimulated insulin secretion” (FASIS) is induced by acute FFA uptake and oxidation through the activation of cellular energy production [ 72 , 158 , 194 ]. Resulting physiological low concentrations of ROS are also promoting insulin secretion, which is referred to as “redox stimulated insulin secretion” (RSIS) [ 56 ].…”