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Caspases, a family of cysteine-dependent aspartate-specific proteases, are central to the maintenance of cellular and organismal homoeostasis by functioning as key mediators of the inflammatory response and/or apoptosis. Both metabolic inflammation and apoptosis play a central role in the pathogenesis of metabolic disease such as obesity and the progression of nonalcoholic steatohepatisis (NASH) to more severe liver disease. Obesity and nonalcoholic fatty liver disease (NAFLD) are the leading global health challenges associated with the development of numerous comorbidities including insulin resistance, type-2 diabetes and early mortality. Despite the high prevalence, current treatment strategies including lifestyle, dietary, pharmaceutical and surgical interventions, are often limited in their efficacy to manage or treat obesity, and there are currently no clinical therapies for NAFLD/NASH. As mediators of inflammation and cell death, caspases are attractive therapeutic targets for the treatment of these metabolic diseases. As such, pan-caspase inhibitors that act by blocking apoptosis have reached phase I/II clinical trials in severe liver disease. However, there is still a lack of knowledge of the specific and differential functions of individual caspases. In addition, cross-talk between alternate cell death pathways is a growing concern for long-term caspase inhibition. Evidence is emerging of the important cell-death-independent, non-apoptotic functions of caspases in metabolic homoeostasis that may be of therapeutic value. Here, we review the current evidence for roles of caspases in metabolic disease and discuss their potential targeting as a therapeutic strategy. Refereed/Peer-reviewed

Caspase-2 is an initiator caspase, which has been implicated to function in apoptotic and non-apoptotic signalling pathways, including cell-cycle regulation, DNA-damage signalling and tumour suppression. We previously demonstrated that caspase-2 deficiency enhances E1A/Ras oncogene-induced cell transformation and augments lymphomagenesis in the EμMyc mouse model. Caspase-2(-/-) mouse embryonic fibroblasts (casp2(-/-) MEFs) show aberrant cell-cycle checkpoint regulation and a defective apoptotic response following DNA damage. Disruption of cell-cycle checkpoints often leads to genomic instability (GIN), which is a common phenotype of cancer cells and can contribute to cellular transformation. Here we show that caspase-2 deficiency results in increased DNA damage and GIN in proliferating cells. Casp2(-/-) MEFs readily escape senescence in culture and exhibit increased micronuclei formation and sustained DNA damage during cell culture and following γ-irradiation. Metaphase analyses demonstrated that a lack of caspase-2 is associated with increased aneuploidy in both MEFs and in EμMyc lymphoma cells. In addition, casp2(-/-) MEFs and lymphoma cells exhibit significantly decreased telomere length. We also noted that loss of caspase-2 leads to defective p53-mediated signalling and decreased trans-activation of p53 target genes upon DNA damage. Our findings suggest that loss of caspase-2 serves as a key function in maintaining genomic integrity, during cell proliferation and following DNA damage.