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Chronotherapy with ...
Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats
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- Kroon, Tobias (author)
- Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine
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Hagstedt, T. (author)
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Alexandersson, I. (author)
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Ferm, A. (author)
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Petersson, M. (author)
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Maurer, S. (author)
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Zarrouki, B. (author)
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Wallenius, K. (author)
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Oakes, N. D. (author)
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- Boucher, Jeremie (author)
- Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine
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(creator_code:org_t)
- American Association for the Advancement of Science (AAAS), 2022
- 2022
- English.
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In: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 14:668
- Related links:
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https://doi.org/10.1...
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Abstract
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- Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- total lipid extraction
- de-novo lipogenesis
- glucose-homeostasis
- insulin-resistance
- regulatory protein
- circadian-rhythms
- fatty liver
- bume method
- triglyceride
- mutation
- Cell Biology
- Research & Experimental Medicine
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Kroon, Tobias
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Hagstedt, T.
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Alexandersson, I ...
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Ferm, A.
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Petersson, M.
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Maurer, S.
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show more...
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Zarrouki, B.
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Wallenius, K.
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Oakes, N. D.
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Boucher, Jeremie
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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- By the university
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University of Gothenburg