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. 2020 Jun 25;12(12):11337-11348.
doi: 10.18632/aging.103607. Epub 2020 Jun 25.

Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/quercetin

Arantzazu Sierra-Ramirez  1 , José Luis López-Aceituno  1 , Luis Filipe Costa-Machado  1 , Adrián Plaza  1 , Marta Barradas  1 , Pablo Jose Fernandez-Marcos  1
Affiliations

Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/quercetin

Arantzazu Sierra-Ramirez et al. Aging (Albany NY). .

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.

Keywords: diabetes; mouse model; obesity; senescence; senolytic.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Senolytic treatment strategy. (A) Scheme of the senolytic treatments strategy: C57BL/6HsdOla male mice of 12 weeks of age were fed on 45% HFD for 4 months. Then, 5 cycles of senolytic treatment and glucose homeostasis assessment were undertaken: first, mice were treated daily by oral gavage with the senolytic or its vehicle for 5 consecutive days, and rested for 1 week. The third week of each cycle, an insulin tolerance test (I) and a glucose tolerance test (G) were performed. After the fifth cycle was finished, mice were treated again with senolytics for 5 consecutive days by oral gavage, and sacrificed at the fifth day of treatment (Sac). (B) Mouse body weight at the first day of every senolytic treatment, indicated for each of the 5 cycles. (C) Food intake recorded at cycles 1 and 2. (D) Blood samples were collected every fifth day of each cycle of senolytic treatments, right after the last oral administration, and platelet counts were determined. V-Nav: vehicle for navitoclax. Nav: navitoclax. V-D/Q: vehicle for dasatinib/quercetin. D/Q: dasatinib/quercetin. Bars and dots represent the average of the indicated number of mice. Error bars represent the standard error of the mean (s.e.m.). Statistical significance was assessed using the two-way ANOVA test with Sidak’s correction for multiple comparisons (B); the one-way ANOVA test with Tukey’s correction for multiple comparisons (C); or the unpaired two-tailed Student's t-test (D). **, p<0.01; ***, p<0.001.
Figure 2
Figure 2
Senescence markers in DIO-mice after senolytic treatment. (A) Macroscopic view of perigonadal white adipose tissue (pWAT) from mice treated with the 5 cycles of senolytics and stained for senescence-associated β-Galactosidase (SA-β-Gal) activity. V: vehicle. Nav: navitoclax. D/Q:dasatinib/quercetin. (B) Microscopic images of the same pWATs shown in (A). (C) Quantification of the blue area, positive for SA-βGal, of 6 fields per condition from the pWATs shown in (A) and (B). (D) mRNA expression analysis of the indicated genes in pWAT obtained at the day of sacrifice. Statistical significance was assessed using the one-way ANOVA test with Tukey's correction for multiple comparisons (C) or the two-tailed unpaired Student's t-test between each treatment and its control (D) Asterisks refer to the comparison with the corresponding vehicle-treated mice. *, p<0.05; **, p<0.01.
Figure 3
Figure 3
Metabolic phenotyping of mice treated with senolytics. Glucose (A and C) and insulin (B and D) tolerance tests performed at the indicated cycles. The area under the curve (AUC) was calculated for each experiment and represented in the insets. (E) Representative examples (n=3 from a total of n=6) of Western blots of the indicated proteins from plasma obtained at cycle 4 from the same mice shown in (A–D). (F) Quantification of Western blots for adiponectin, including those represented in (E), from all available plasma samples from mice shown in (A–D) (n=6). (G) mRNA expression analysis of the indicated genes in pWAT obtained at the day of sacrifice. Bars and dots represent the average of the indicated number of mice per group. Error bars represent the standard error of the mean. Statistical significance was assessed by the two-way ANOVA test with Sidak’s correction for multiple comparisons for the time course experiments (main graphs at A–D); and with the two-tailed unpaired Student's t-test for the AUC data (A–D) and for panels E and F. Asterisks refer to the comparison with the corresponding vehicle-treated mice. *, p<0.05.
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