Divergent roles for caspase-8 and MLKL in high-fat diet induced obesity and NAFLD in mice
Cell death frequently occurs in the pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill defined. Here, we show via the direct comparison of mice genetically deficient in apoptotic caspase-8 in myeloid cells, or the essential necroptotic regulators, Receptor-interacting protein kinase-3 (RIPK3) and Mixed lineage kinase domain-like (MLKL), that RIPK3-caspase-8 signaling regulates macrophage inflammatory responses and drives adipose tissue inflammation and NAFLD upon high-fat diet feeding. In contrast, MLKL, divergent to RIPK3, contributes to both obesity and NAFLD in a manner largely independent of inflammation. We also uncover that MLKL regulates the expression of molecules involved in lipid uptake, transport and metabolism and, congruent with this, we discover a shift in the hepatic lipidome upon MLKL deletion. Collectively, these findings highlight MLKL as an attractive therapeutic target to combat the growing obesity pandemic and metabolic disease. Overall design: Eight- to nine-week old Wild-type and Mlkl-/- mice were fed either a high-fat diet (HFD; 36% fat, 59% of total energy from lipid; Specialty Feeds, WA, Australia) or a normal chow diet (ND) ad libitum for 16-25 weeks. Liver RNA was extracted from fed animal (selected based on mean organ weights) using Trizol RNA Isolation Reagents and purified using RNeasy Mini Kit (QIAGEN).