Caspase-2 is an important proteolytic enzyme that functions in both apoptotic and non-apoptotic signalling pathways affecting oxidative stress, genomic stability, ageing and cancer. Caspase-2 deficient (Casp2-/-) mice display several premature ageing related traits and altered bodycomposition (decreased fat mass and skeletal muscle). Using comparative “omics” profiling we found that caspase-2 contributes to ageing by regulating basal metabolism, proteostasis and oxidative stress [1]. We observed altered mitochondrial function, reduced levels of liver free fatty acids (FFA), glycerol-3 phosphate (G3P) and acetyl-CoA carboxylase 1 (ACC1) protein indicating perturbation of lipid metabolism. Intriguingly, we found that aged male Casp2-/-mice, but not females, display resistance to age-induced glucose intolerance. In this present study we have used 18 hour fasting to stimulate lipolysis in young (16 weeks) and aged (18-24 months) male and female WT and Casp2-/-mice to further investigate the role of caspase-2 in lipid metabolism and energy homeostasis. Fasting of Casp2-/- mice,significantly reduced white adipocyte size and increased serum FFA compared to WT suggesting an increased rate of lipolysis.In male Casp2-/- mice only, fasting significantly reduced the liver/body weight ratio compared to WT. Fasting increased autophagy in livers of Casp2-/-mice. Further analysis of our findings will be presented at this meeting. Our results suggest an important novel role for caspase-2 as a regulator of lipid metabolism and altered utilisation of fat as fuel source. Furthermore, they suggest that therapeutic targeting of caspase-2 may be a possibility in the treatment and prevention of obesity.
[1] Wilson CH, Shalini S, Filipovska A, Richman TR, Davies S, Martin SD, McGee SL, Puccini J, Nikolic A, Dorstyn L, Kumar S. Age-related proteostasis and metabolic alterations in Caspase-2-deficient mice. Cell Death and Disease. 2015, 6: e1597