Mitochondrially targeted tamoxifen improves diet-induced obesity and diabetes and reduces adipose tissue senescence in experimental mice

Abstract

Background and aims: Diabetes and ageing are mutually linked and senescent cells might be involved in the development of obesity and type 2 diabetes mellitus (T2DM). Recent studies have shown that senolytic agents may improve diabetes-related pathologies. To this end we have tested our novel anti-cancer agent with senolytic properties, mitochondrially targeted tamoxifen (MitoTam), in a mouse model of T2DM.

Materials and methods: Obesity and diabetic metabolic profile were induced by high fat diet (HFD) feeding in 20 C57BL/6J male mice for 6 months with another group fed a standard diet (SD) serving as controls. Subsequently, both groups were divided into 2 subgroups (n=10 each) treated either with MitoTam (2μg/1g of body weight dissolved in 4% ethanol in corn oil) or the excipient given i.p. twice a week for a period of 4 weeks.

Results: In HFD animals, MitoTam (MT) decreased body weight already after 2 weeks of treatment, with most pronounced reduction of visceral adipose tissue (VAT, P<0.001), whereas it had no effect on body weight in SD group. MitoTam also reduced fasting glucose (HFD+MT: 6.2±0.4 vs. HFD: 9.8±0.4 (mmol/l); P<0.001) as well as postprandial glucose AUC (HFD+MT: 1517±57 vs. HFD: 2309±111 (mmol/l x min); P<0.001) of HFD mice to levels comparable with SD group. This glucose-lowering effect was accompanied by a decrease in serum triglycerides (P<0.002), insulin (P<0.002), leptin (P<0.001) and glucose-dependent insulinotropic peptide (GIP, P<0.03) together with reduction of mRNA expression of leptin in epididymal adipose tissue (EAT, P<0.001), EAT adipocyte size and lipid accumulation in the liver (P<0.002). HFD-induced obesity and T2DM phenotype was associated with elevated levels of senescent markers p16 and β-gal in EAT (P<0.001 for p16 and P<0.03 for β-gal vs. SD), both of which were markedly reduced by MitoTam treatment (P<0.001 for p16 and P<0.002 for β-gal vs. HFD).

Conclusion: In conclusion, our results suggest that MitoTam significantly improves HFD-induced obesity and diabetes in mice and that this effect might be in part mediated by alleviated senescence in adipose tissue.