Scripties UMCG - Rijksuniversiteit Groningen
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Effects of the senolytics Dasatinib and Quercetin on glucose and lipid metabolism in db/db mice

(2018) Verkade, E.

Background & aims: Obesity, classified as a BMI >30 kg/m2, constitutes a growing health problem throughout the world. The chronic low-grade inflammation associated with obesity is a major risk factor for both type II diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). It is currently hypothesized that cellular senescence, i.e., irreversible cessation of cell replication, resistance to apoptosis and a senescence-associated secretory phenotype (SASP), is the driving mechanism behind the low-grade inflammation found in obese subjects. Previous studies showed that the tyrosine kinase inhibitor Dasatinib (D) and the potent antioxidant flavonoid Quercetin (Q) have the potency to ablate cellular senescence and to improve the metabolic profile regarding hepatic fat deposition and glucose metabolism. The aim of this study was to quantify the effects of D + Q administration on glucose metabolism and hepatic lipid accumulation in obese db/db mice. Methods: D (5 mg/kg) + Q (50 mg/kg) or its solvent (60% Phosal, 10% ethanol, 30% PEG-400) was administered by oral gavage to db/db mice. Four sessions of five consecutive treatment days were alternated by four to five rest days. Whole body glucose tests and a hyperinsulemic euglycemic clamp were performed to assess the glucose metabolism. In addition, liver histology was examined and hepatic lipid content was quantified. Gonadal white adipose tissue was also collected. Results: In mice the D + Q treatment led to a minor increase in total body insulin sensitivity. Apart from this, the whole body glucose tests, hyperinsulemic euglycemic clamp, liver histology examination and liver lipid analyses did not reveal additional metabolic benefits upon D + Q treatment in db/db mice. Conclusions: Our data presents different effects of D + Q treatment compared to previous studies, possibly due to the inclusion of older animals, a different treatment scheme, slight variation in genetic background and/or a divergent nutritional status. This study stresses the requirement of further research into these agents.

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