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Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.<\/jats:p>","DOI":"10.1126\/scitranslmed.abh1316","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T17:58:45Z","timestamp":1666807125000},"source":"Crossref","is-referenced-by-count":20,"title":["Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5110-4916","authenticated-orcid":true,"given":"Tobias","family":"Kroon","sequence":"first","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."},{"name":"Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothernburg 41345, Sweden."},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothernburg 40530 Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3516-4665","authenticated-orcid":true,"given":"Therese","family":"Hagstedt","sequence":"additional","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3038-3893","authenticated-orcid":true,"given":"Ida","family":"Alexandersson","sequence":"additional","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annett","family":"Ferm","sequence":"additional","affiliation":[{"name":"Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Petersson","sequence":"additional","affiliation":[{"name":"Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9737-4962","authenticated-orcid":true,"given":"Stefanie","family":"Maurer","sequence":"additional","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bader","family":"Zarrouki","sequence":"additional","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3231-2733","authenticated-orcid":true,"given":"Kristina","family":"Wallenius","sequence":"additional","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D.","family":"Oakes","sequence":"additional","affiliation":[{"name":"Functional and Mechanistic Safety, Clinical Pharmacology and Safety Sciences, R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9610-475X","authenticated-orcid":true,"given":"Jeremie","family":"Boucher","sequence":"additional","affiliation":[{"name":"Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca, Gothenburg 43183, Sweden."},{"name":"Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothernburg 41345, Sweden."},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothernburg 40530 Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.04.015"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.034"},{"key":"e_1_3_3_4_2","first-page":"E1130","article-title":"Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss","volume":"277","author":"Kelley D. 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