Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/quercetin
Arantzazu Sierra-Ramirez1, José Luis López-Aceituno1, Luis Filipe Costa-Machado1
1Metabolic Syndrome Group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain.
Abstract:
Senescent cells accumulate with obesity in the white adipose tissue of mice and humans. These senescent cells enhance the pro-inflammatory environment that, with time, contributes to the onset of glucose intolerance and type 2 diabetes. Glucose intolerance in mouse models of obesity has been successfully reversed by the elimination of senescent cells with the senolytic compounds navitoclax or the combination of dasatinib and quercetin (D/Q). In this work, we generated obese mice by high-fat diet feeding, and treated them with five consecutive cycles of navitoclax or D/Q during 16 weeks. We observed an efficient reduction in the white adipose tissue of the senescence markers senescence-associated β-galactosidase activity, Cdkn2a-p16 and Cdkn2a-p19 at the end of the 5 cycles. Mice treated with both navitoclax and D/Q showed an improvement of their insulin sensitivity and glucose tolerance during a short period of time (cycles 3 and 4), that disappeared at the fifth cycle. Also, these mice tended to increase the expression at their adipose tissue of the adipogenic genes Pparg and, Cebpa, as well as their plasma adiponectin levels. Together, our work shows that two different senolytic treatments, acting through independent pathways, are transiently effective in the treatment of obesity-induced metabolic disorders.
Insights
Senescent cells in obesity worsen inflammation and glucose intolerance. Senolytic treatments temporarily improved metabolic disorders in mice, but effects were not sustained long-term.
Area of Science:
- Metabolic disorders
- Cellular senescence
- Obesity research
Background:
- Senescent cells accumulate in white adipose tissue with obesity.
- This accumulation promotes inflammation, contributing to glucose intolerance and type 2 diabetes.
- Senolytic drugs have shown promise in reversing obesity-induced glucose intolerance.
Purpose of the Study:
- To investigate the efficacy of senolytic treatments (navitoclax or dasatinib/quercetin) in obese mice.
- To assess the impact of these treatments on senescence markers and metabolic parameters.
- To determine the duration of therapeutic effects.
Main Methods:
- Obese mice were induced via high-fat diet and treated with navitoclax or dasatinib/quercetin for 16 weeks (5 cycles).
- Senescence markers (SA-β-gal, p16, p19) in white adipose tissue were measured.
- Insulin sensitivity, glucose tolerance, adipogenic gene expression (Pparg, Cebpa), and plasma adiponectin were assessed.
Main Results:
- Both treatments effectively reduced senescence markers in white adipose tissue.
- Transient improvements in insulin sensitivity and glucose tolerance were observed during cycles 3 and 4.
- These metabolic improvements diminished by the fifth treatment cycle.
- Treated mice showed a trend towards increased adipogenic gene expression and adiponectin levels.
Conclusions:
- Senolytic treatments navitoclax and dasatinib/quercetin show transient efficacy in ameliorating obesity-induced metabolic dysfunction.
- The therapeutic benefits of these senolytic agents in metabolic disorders appear to be temporary.
- Further research is needed to understand the mechanisms behind the transient effects and to develop sustained therapeutic strategies.
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