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Glucose is a ubiquitous and essential source of energy for all living organisms. Although mammals have evolved ways to convert other nutritional molecules to ATP, the preference for dietary glucose appears to be preserved. In rodents, the immediate detection of ingested glucose potently reinforces intake, hierarchically organizing behaviors towards glucose-yielding substances, and away from other types of food including other sugars. Taste is the primary sense linked to nutrient selection. Until recently, it was thought that most mammalian species utilize a single broadly tuned receptor to detect all simple sugars. Indeed, this “sweet” receptor, which comprises a heterodimer of the T1R2 and T1R3 proteins, binds multiple natural sugars (e.g., glucose, fructose, sucrose, maltose), as well as various other chemicals that yield little to no energy (e.g., low calorie sweeteners, sugar alcohols) and some d-amino acids. The neural signal originating from the sweet receptor is hardwired into brain circuits that drive eating and drinking behaviors, but it is an unreliable indicator of nutrient quality and quantity.

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Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders

Tábatha de Oliveira Silva, Guilherme Lunardon, Caroline A. Lino, Amanda de Almeida Silva, ... Gabriela P. Diniz

Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders

Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managing senescence in obesity-related metabolic and cardiac disorders remains to be fully defined.

Objective

We investigated the beneficial effects of a senolytic cocktail (dasatinib and quercetin) on senescence and its influence on obesity-related parameters.

Methods and Results

We found that the increase in body weight and adiposity, glucose intolerance, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic disorders which were induced by an obesogenic diet were alleviated by senolytic cocktail treatment in mice. Treatment with senolytic compounds eliminated senescent cells, counteracting the activation of the senescence program and DNA damage in white adipose tissue (WAT) observed with an obesogenic diet. Moreover, the senolytic cocktail prevented the brown adipose tissue (BAT) whitening and increased the expression of the thermogenic gene profile in BAT and pWAT. In the hearts of obese mice, senolytic combination abolished myocardial maladaptation, reducing the senescence-associated secretory phenotype (SASP) and DNA damage, repressing cardiac hypertrophy, and improving diastolic dysfunction. Additionally, we showed that treatment with the senolytic cocktail corrected gene expression programs associated with fatty acid metabolism, oxidative phosphorylation, the P53 pathway, and DNA repair, which were all downregulated in obese mice.

Conclusions

Collectively, these data suggest that a senolytic cocktail can prevent the activation of the senescence program in the heart and WAT and activate the thermogenic program in BAT. Our results suggest that targeting senescent cells may be a novel therapeutic strategy for alleviating obesity-related metabolic and cardiac disorders.

Articles in Press

Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders

Tábatha de Oliveira Silva, Guilherme Lunardon, Caroline A. Lino, Amanda de Almeida Silva, ... Gabriela P. Diniz

Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders

Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managing senescence in obesity-related metabolic and cardiac disorders remains to be fully defined.

Objective

We investigated the beneficial effects of a senolytic cocktail (dasatinib and quercetin) on senescence and its influence on obesity-related parameters.

Methods and Results

We found that the increase in body weight and adiposity, glucose intolerance, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic disorders which were induced by an obesogenic diet were alleviated by senolytic cocktail treatment in mice. Treatment with senolytic compounds eliminated senescent cells, counteracting the activation of the senescence program and DNA damage in white adipose tissue (WAT) observed with an obesogenic diet. Moreover, the senolytic cocktail prevented the brown adipose tissue (BAT) whitening and increased the expression of the thermogenic gene profile in BAT and pWAT. In the hearts of obese mice, senolytic combination abolished myocardial maladaptation, reducing the senescence-associated secretory phenotype (SASP) and DNA damage, repressing cardiac hypertrophy, and improving diastolic dysfunction. Additionally, we showed that treatment with the senolytic cocktail corrected gene expression programs associated with fatty acid metabolism, oxidative phosphorylation, the P53 pathway, and DNA repair, which were all downregulated in obese mice.

Conclusions

Collectively, these data suggest that a senolytic cocktail can prevent the activation of the senescence program in the heart and WAT and activate the thermogenic program in BAT. Our results suggest that targeting senescent cells may be a novel therapeutic strategy for alleviating obesity-related metabolic and cardiac disorders.

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13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026

2024 impact factor: 6.6

You are what you eat

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