Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice

Eliska Vacurova, Jaroslava Trnovska, Petr Svoboda, Vojtech Skop, Vendula Novosadova, David Pajuelo Reguera, Silvia Petrezselyová, Benoit Piavaux, Berwini Endaya, Frantisek Spoutil, Dagmar Zudova, Jan Stursa, Magdalena Melcova, Zuzana Bielcikova, Lukas Werner, Jan Prochazka, Radislav Sedlacek, Martina Huttl, Sona Stemberkova Hubackova (), Martin Haluzik () and Jiri Neuzil ()
Additional contact information
Eliska Vacurova: Czech Academy of Sciences
Jaroslava Trnovska: Institute for Clinical and Experimental Medicine
Petr Svoboda: Institute for Clinical and Experimental Medicine
Vojtech Skop: National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Vendula Novosadova: Czech Academy of Sciences
David Pajuelo Reguera: Czech Academy of Sciences
Silvia Petrezselyová: Czech Academy of Sciences
Benoit Piavaux: Czech Academy of Sciences
Berwini Endaya: Czech Academy of Sciences
Frantisek Spoutil: Czech Academy of Sciences
Dagmar Zudova: Czech Academy of Sciences
Jan Stursa: Czech Academy of Sciences
Magdalena Melcova: University of Chemistry and Technology Prague
Zuzana Bielcikova: General University Hospital
Lukas Werner: Czech Academy of Sciences
Jan Prochazka: Czech Academy of Sciences
Radislav Sedlacek: Czech Academy of Sciences
Martina Huttl: Institute for Clinical and Experimental Medicine
Sona Stemberkova Hubackova: Czech Academy of Sciences
Martin Haluzik: Institute for Clinical and Experimental Medicine
Jiri Neuzil: Czech Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Type 2 diabetes mellitus represents a major health problem with increasing prevalence worldwide. Limited efficacy of current therapies has prompted a search for novel therapeutic options. Here we show that treatment of pre-diabetic mice with mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, improves glucose tolerance and reduces body weight with most pronounced reduction of visceral adipose tissue due to reduced food intake, suppressed adipogenesis and elimination of senescent cells. Glucose-lowering effect of mitochondrially targeted tamoxifen is linked to improvement of type 2 diabetes mellitus-related hormones profile and is accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues, as well as its inhibitory effect on pre-adipocyte differentiation, results in lower level of circulating inflammatory mediators that typically enhance metabolic dysfunction. Targeting senescence with mitochodrially targeted tamoxifen thus represents an approach to the treatment of type 2 diabetes mellitus and its related comorbidities, promising a complex impact on senescence-related pathologies in aging population of patients with type 2 diabetes mellitus with potential translation into the clinic.

Date: 2022
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DOI: 10.1038/s41467-022-29486-z

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