The necroptosis-inducing pseudokinase mixed lineage kinase domain-like regulates the adipogenic differentiation of pre-adipocytes

Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domainlike (MLKL) proteins are key regulators of necroptosis, a highly pro-inflammatory mode of cell death, which has been involved in various human diseases. Necroptotic- independent functions of RIPK3 andMLKL also exist, notably in the adipose tissue but remain poorly defined. Using knock-out (KO) cell models, we investigated the role of RIPK3 andMLKL in adipocyte differentiation. Mlkl-KOabolished white adipocyte differentiation via a strong expression ofWnt10b, a ligand of the Wnt/b-catenin pathway, and a downregulation of genes involved in lipid metabolism. This effect was not recapitulated by the ablation of Ripk3. Conversely, Mlkl and Ripk3 deficiencies did not block beige adipocyte differentiation. These findings indicate that RIPK3 and MLKL have distinct roles in adipogenesis. The absence of MLKL blocks the differentiation of white, but not beige, adipocytes highlighting the therapeutic potential of MLKL inhibition in obesity.

Automated summary

RIPK3 and MLKL have distinct roles in adipocyte differentiation, with MLKL deficiency blocking white adipocyte differentiation but not beige adipocyte differentiation, highlighting the therapeutic potential of MLKL inhibition in obesity.