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.

Centre for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague Prague Czech Republic

Diabetes Centre Institute for Clinical and Experimental Medicine Prague Czech Republic

Diabetes Endocrinology and Obesity Branch National Institute of Diabetes and Digestive and Kidney Diseases NIH Bethesda MD 20892 USA

Faculty of Science Charles University Prague Czech Republic

General University Hospital Prague Czech Republic

Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

Institute of Molecular Genetics Czech Academy of Sciences Prague West Czech Republic

School of Pharmacy and Medical Science Griffith University Southport QLD Australia

Zobrazit více v PubMed

Ogurtsova K, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract. 2017;128:40–50. PubMed

Wilkinson E, Waqar M, Sinclair A, Randhawa G. Meeting the challenge of diabetes in ageing and diverse populations: a review of the literature from the UK. J. Diabetes Res. 2016;2016:8030627. PubMed PMC

Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017;389:2239–2251. PubMed

Schnurr, T. M. et al. Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: a case-cohort study. Diabetologia63, 1324–1332 (2020). PubMed

Bluher M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best. Pract. Res. Clin. Endocrinol. Metab. 2013;27:163–177. PubMed

Mraz M, Haluzik M. The role of adipose tissue immune cells in obesity and low-grade inflammation. J. Endocrinol. 2014;222:R113–R127. PubMed

Luo L, Liu M. Adipose tissue in control of metabolism. J. Endocrinol. 2016;231:R77–R99. PubMed PMC

Ravussin E, Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann. N. Y Acad. Sci. 2002;967:363–378. PubMed

Palmer AK, et al. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes. 2015;64:2289–2298. PubMed PMC

Munoz-Espin D, Serrano M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 2014;15:482–496. PubMed

Sabin RJ, Anderson RM. Cellular senescence - its role in cancer and the response to ionizing radiation. Genome Integr. 2011;2:7. PubMed PMC

Tchkonia T, et al. Fat tissue, aging, and cellular senescence. Aging Cell. 2010;9:667–684. PubMed PMC

Sone H, Kagawa Y. Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia. 2005;48:58–67. PubMed

Palmer AK, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019;18:e12950. PubMed PMC

Minamino T, et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 2009;15:1082–1087. PubMed

Ogrodnik M, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 2017;8:15691. PubMed PMC

Bratic A, Larsson NG. The role of mitochondria in aging. J. Clin. Invest. 2013;123:951–957. PubMed PMC

Hubackova S, et al. Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death Differ. 2019;26:276–290. PubMed PMC

Rohlenova K, et al. Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2high breast cancer. Antioxid. Redox Signal. 2017;26:84–103. PubMed PMC

Maedler K, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 2017;127:1589. PubMed PMC

Mauer J, et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 2014;15:423–430. PubMed PMC

Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–867. PubMed

Perez LM, et al. ‘Adipaging’: ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue. J. Physiol. 2016;594:3187–3207. PubMed PMC

Petro AE, et al. Fat, carbohydrate, and calories in the development of diabetes and obesity in the C57BL/6J mouse. Metabolism. 2004;53:454–457. PubMed

Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes. 1988;37:1163–1167. PubMed

Bargut, T. C. L., Souza-Mello, V., Aguila, M. B. & Mandarim-de-Lacerda, C. A. Browning of white adipose tissue: lessons from experimental models. Horm. Mol. Biol. Clin. Investig.31 (2017). PubMed

Berry DC, Jiang Y, Graff JM. Emerging roles of adipose progenitor cells in tissue development, homeostasis, expansion and thermogenesis. Trends Endocrinol. Metab. 2016;27:574–585. PubMed PMC

Hwang SH, Lee M. Autophagy inhibition in 3T3-L1 adipocytes breaks the crosstalk with tumor cells by suppression of adipokine production. Anim. Cells Syst. (Seoul.) 2020;24:17–25. PubMed PMC

Skop V, et al. Autophagy inhibition in early but not in later stages prevents 3T3-L1 differentiation: Effect on mitochondrial remodeling. Differentiation. 2014;87:220–229. PubMed

Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol. Rev. 1998;78:783–809. PubMed

Patel YM, Lane MD. Mitotic clonal expansion during preadipocyte differentiation: calpain-mediated turnover of p27. J. Biol. Chem. 2000;275:17653–17660. PubMed

Tang QQ, Otto TC, Lane MD. Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc. Natl. Acad. Sci. USA. 2003;100:44–49. PubMed PMC

Wilson-Fritch L, et al. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol. Cell Biol. 2003;23:1085–1094. PubMed PMC

Drehmer DL, et al. Metabolic switches during the first steps of adipogenic stem cells differentiation. Stem Cell Res. 2016;17:413–421. PubMed

Lee YS, et al. Increased adipocyte O2 consumption triggers HIF-1alpha, causing inflammation and insulin resistance in obesity. Cell. 2014;157:1339–1352. PubMed PMC

Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia. 2019;62:3–16. PubMed

de Vos LC, Hettige TS, Cooper ME. New glucose-lowering agents for diabetic kidney disease. Adv. Chronic Kidney Dis. 2018;25:149–157. PubMed

Patti, A. M. et al. Impact of glucose-lowering medications on cardiovascular and metabolic risk in type 2 diabetes. J. Clin. Med.9, 912 (2020). PubMed PMC

Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20:953–966. PubMed

Foretz M, Viollet B. Therapy: metformin takes a new route to clinical efficacy. Nat. Rev. Endocrinol. 2015;11:390–392. PubMed PMC

Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23:1060–1065. PubMed PMC

Justice JN, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554–563. PubMed PMC

Wade GN, Heller HW. Tamoxifen mimics the effects of estradiol on food intake, body weight, and body composition in rats. Am. J. Physiol. 1993;264:R1219–R1223. PubMed

Hesselbarth N, et al. Tamoxifen affects glucose and lipid metabolism parameters, causes browning of subcutaneous adipose tissue and transient body composition changes in C57BL/6NTac mice. Biochem. Biophys. Res. Commun. 2015;464:724–729. PubMed

Sheean PM, Hoskins K, Stolley M. Body composition changes in females treated for breast cancer: a review of the evidence. Breast Cancer Res. Treat. 2012;135:663–680. PubMed PMC

Lipscombe LL, et al. Association between tamoxifen treatment and diabetes: a population-based study. Cancer. 2012;118:2615–2622. PubMed

Warnakulasuriya LS, et al. Metformin in the management of childhood obesity: a randomized control trial. Child Obes. 2018;14:553–565. PubMed

Jain SS, et al. Evaluation of efficacy and safety of orlistat in obese patients. Indian J. Endocrinol. Metab. 2011;15:99–104. PubMed PMC

Kelly, A. S. et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N. Engl. J. Med.382, 2117–2128 (2020). PubMed

Bar-Ziv R, Bolas T, Dillin A. Systemic effects of mitochondrial stress. EMBO Rep. 2020;21:e50094. PubMed PMC

Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annu Rev. Cell Dev. Biol. 2000;16:145–171. PubMed

De Pauw A, Tejerina S, Raes M, Keijer J, Arnould T. Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am. J. Pathol. 2009;175:927–939. PubMed PMC

Vernochet C, et al. Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab. 2012;16:765–776. PubMed PMC

Zhao X, et al. Leptin changes differentiation fate and induces senescence in chondrogenic progenitor cells. Cell Death Dis. 2016;7:e2188. PubMed PMC

Tencerova M, et al. Obesity-associated hypermetabolism and accelerated senescence of bone marrow stromal stem cells suggest a potential mechanism for bone fragility. Cell Rep. 2019;27:2050–2062 e2056. PubMed

Perez-Riverol Y, et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 2022;50:D543–D552. PubMed PMC

Accumulation of chlorinated paraffins in adipocytes is determined by cellular lipid content and chlorination level