Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders

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Silva, Tabatha de Oliveira ; Lunardon, Guilherme ; Lino, Caroline A. ; Silva, Amanda de Almeida ; Zhang, Shiju ; Irigoyen, Maria Claudia Costa ; Lu, Yao Wei ; Mably, John D. ; Barreto-Chaves, Maria Luiza M. ; Wang, Da-Zhi ; Diniz, Gabriela P.

• Document type: Journal article
• Source: MOLECULAR METABOLISM; v. 91, p. 15-pg., 2024-11-27.

Abstract

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. (c) 2024 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). (AU)

• FAPESP's process: 22/10060-0 - Impact of SET7 on pathological cardiac remodeling
• Grantee: Guilherme Lunardon
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/13211-3 - Impact of microRNA-22 and cellular senescence in obesity-induced metabolic dysfunctions
• Grantee: Gabriela Placoná Diniz
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/14289-6 - Impact of cellular senescence in Obesity-induced cardiovascular and metabolic dysfunctions in female mice
• Grantee: Tábatha de Oliveira Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 23/03444-9 - MicroRNAs as potential targets for treatment of obesity-induced cardiac hypertrophy
• Grantee: Gabriela Placoná Diniz
• Support Opportunities: Scholarships abroad - Research
• FAPESP's process: 23/02585-8 - Role of the senescence in obesity-induced cardiac hypertrophy and the influence of the microRNAs
• Grantee: Tábatha de Oliveira Silva
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate