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.
Highlights
Obesity has become a worldwide health problem, with an incidence that has nearly tripled since 1975 [1]
To generate the mouse model of diet-induced obesity (DIO), we fed a cohort of 32 male mice of the C57BL/6OlaHsd background on a high-fat diet (HFD, 45% fat) for 4 months until they reached obesity
We performed 5 cycles of treatments, each cycle beginning with 5 consecutive days of administration of senolytics and their vehicles by oral gavage, followed by one week of rest, and a final week when we performed one insulin tolerance test (ITT) and one glucose tolerance test (GTT)
Summary
Obesity has become a worldwide health problem, with an incidence that has nearly tripled since 1975 [1]. It is defined as an imbalance between energy intake and expenditure that, when maintained in time, causes a systemic chronic inflammation that degenerates in obesityassociated insulin resistance and type 2 diabetes [2]. The definition of senescence has evolved significantly, and it is generally accepted that senescence is a stable proliferative arrest caused by some stresses such as telomere dysfunction, oxidative stress, DNA damage, oncogene activation or cytotoxic drugs [7, 8]. The most frequently used biomarker to detect senescent cells is the lysosomal β-galactosidase enzyme activity at a suboptimal pH 6.0, known as senescence-associated βgalactosidase staining (SA-βGal) [11]
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