British journal of pharmacology · 2020
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.
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Chen Yueming, Ren Qiang, Zhou Zongtao, Deng Liming, Hu Lijun, Zhang Luyong, Li Zheng
Аннотация
BACKGROUND AND PURPOSE: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive anti-diabetic target. This study characterizes the pharmacological profile of HWL-088 (2-(2-fluoro-4-((2'-methyl-[1,1'- biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the long-term 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 (EC50 = 18.9 nM) with moderate PPARδ activity (EC50 = 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.
CONCLUSION AND IMPLICATIONS: These data indicate that long-term treatment with HWL-088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with metformin.
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 (EC50 = 18.9 nM) with moderate PPARδ activity (EC50 = 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.
CONCLUSION AND IMPLICATIONS: These data indicate that long-term treatment with HWL-088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with metformin.