{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T18:21:01Z","timestamp":1769019661414,"version":"3.49.0"},"reference-count":52,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,2,8]],"date-time":"2020-02-08T00:00:00Z","timestamp":1581120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100008366","name":"Guangdong Pharmaceutical University","doi-asserted-by":"publisher","award":["43540073"],"award-info":[{"award-number":["43540073"]}],"id":[{"id":"10.13039\/501100008366","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008366","name":"Guangdong Pharmaceutical University","doi-asserted-by":"publisher","award":["2018KTSCX111"],"award-info":[{"award-number":["2018KTSCX111"]}],"id":[{"id":"10.13039\/501100008366","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81803341"],"award-info":[{"award-number":["81803341"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The free fatty acid receptor 1 (FFAR1) plays an important role in glucose\u2010stimulated insulin secretion making it an attractive anti\u2010diabetic target. This study characterizes the pharmacological profile of HWL\u2010088 (2\u2010(2\u2010fluoro\u20104\u2010((2\u2032\u2010methyl\u2010[1,1\u2032\u2010 biphenyl]\u20103\u2010yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the long\u2010term effects of HWL\u2010088 alone and in combination with metformin in diabetic mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In vitro effects of HWL\u2010088 on FFAR1 and PPAR\u03b1\/\u03b3\/\u03b4 were studied in cell\u2010based assays. Glucose\u2010dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long\u2010term effects on glucose and lipid metabolism were investigated in <jats:italic>ob\/ob<\/jats:italic> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>HWL\u2010088 is a highly potent FFAR1 agonist (EC<jats:sub>50<\/jats:sub> = 18.9 nM) with moderate PPAR\u03b4 activity (EC<jats:sub>50<\/jats:sub> = 570.9 nM) and promotes glucose\u2010dependent insulin secretion in vitro and in vivo. Long\u2010term administration of HWL\u2010088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK\u2010875, and synergistic improvements were observed when combined with metformin. Moreover, HWL\u2010088 and combination therapy improved \u03b2\u2010cell function by up\u2010regulation of pancreas duodenum homeobox\u20101, reduced fat accumulation in adipose tissue and alleviated fatty liver in <jats:italic>ob\/ob<\/jats:italic> mice. The effect of HWL\u2010088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid \u03b2\u2010oxidation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>These data indicate that long\u2010term treatment with HWL\u2010088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono\u2010therapy or combination with metformin.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14980","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T15:51:07Z","timestamp":1579794667000},"page":"2286-2302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["HWL\u2010088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in <i>ob\/ob<\/i> diabetic mice"],"prefix":"10.1111","volume":"177","author":[{"given":"Yueming","family":"Chen","sequence":"first","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"},{"name":"Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zongtao","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liming","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luyong","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"},{"name":"Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province Guangdong Pharmaceutical University  Guangzhou China"},{"name":"Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems Guangdong Pharmaceutical University  Guangzhou China"},{"name":"Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8067-9700","authenticated-orcid":false,"given":"Zheng","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"},{"name":"Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,2,8]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14748"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14750"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14752"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(15)00462-3"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1061"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2005.10.004"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211495200"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19071893"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0b013e328337b0c4"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"issue":"18","key":"e_1_2_11_13_1","first-page":"4600","article-title":"Experimental design and analysis and their reporting: New guidance for publication in BJP (vol 172, pg 3461, 2015)","volume":"172","author":"Curtis M. J.","year":"2015","journal-title":"British Journal of Pharmacology"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60679-X"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.01.045"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-4845-x"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09-9028"},{"issue":"1","key":"e_1_2_11_18_1","first-page":"82","article-title":"New promises for metformin: Advances in the understanding of its mechanisms of action","volume":"30","author":"Foretz M.","year":"2014","journal-title":"M S\u2010Medecine Science"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00035.2005"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.07.043"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200363180-00001"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12297"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01478"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200198200"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.6.1692"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.165472"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2015.08.108"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.01911.x"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510815103"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.12.069"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2016.1189530"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2015.10.011"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21441"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2004.11.011"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12955"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.6b00056"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/549627"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-14-0003"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19030913"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.035568"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.11.5.661"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.2007.S119"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2006.09.013"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.07.042"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2013.752813"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00207-5"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.10.012"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.111.183772"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2014.11.016"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2014.941352"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2013.11.019"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.14980","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.14980","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.14980","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.14980","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,2]],"date-time":"2023-09-02T13:34:13Z","timestamp":1693661653000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.14980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,8]]},"references-count":52,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["10.1111\/bph.14980"],"URL":"https:\/\/doi.org\/10.1111\/bph.14980","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,8]]},"assertion":[{"value":"2019-05-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}