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- Kroon, Tobias, et al.
(författare)
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Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats
- 2022
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Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 14:668
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Zarrouki, B., et al.
(författare)
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An Obesogenic Dietary Mouse Model of Nonalcoholic Steatohepatitis
- 2020
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Ingår i: Kupffer Cells. - New York, NY : Springer US. - 1064-3745.
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), characterized by steatosis (fat within the liver), inflammation, and fibrosis, which may progress to cirrhosis and hepatocellular carcinoma. Despite the high prevalence, there are currently no approved NASH drug treatments, which urges a faster development of new therapies to address this high unmet medical need. Drug development is facilitated by having reliable and translatable preclinical NASH models. Obesogenic dietary models recapitulate better the natural progression of NASH, with overnutrition and sedentary lifestyle being the main causes. Here we describe the use of a modified version of a diet-induced NASH model, known as the Amylin NASH diet model (AMLN-diet), particularly in the leptin-deficient Lepob/Lepob (ob/ob) mice. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
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