DAXX ameliorates metabolic dysfunction in mice with diet-induced obesity by activating the AMP-activated protein kinase-related kinase MPK38/MELK

Death domain-associated protein (DAXX) is involved in the activation of adipocyte apoptosis and is downregulated in response to a high-fat diet (HFD), which implies that the inhibition of adipocyte apoptosis may cause obesity. However, the anti-obesity effects of DAXX in diet-induced obesity (DIO) remain to be characterized. Here, we identified DAXX as an interacting partner of murine protein serine-threonine kinase 38 (MPK38). This interaction was mediated by the C-terminal (amino acids 270–643) domain of MPK38 and the N-terminal (amino acids 1–440) domain of DAXX and was increased by diverse signals that activate ASK1/TGF-β/p53 signaling. MPK38 phosphorylated DAXX at Thr578. Wild-type DAXX, but not a DAXX T578A mutant, stimulated MPK38-dependent ASK1/TGF-β/p53 signaling by increasing the stability of MPK38 and complex formation between MPK38 and its downstream targets, such as ASK1, Smad3, and p53. This mechanism was also shown in MEF cells that were null (−/−) for DAXX. Furthermore, the adenovirally-mediated reinstatement of DAXX expression activated MPK38 and ameliorated diet-induced defects in glucose and lipid metabolism in mice. These results indicate that DAXX limits obesity-induced metabolic abnormalities in DIO mice by activating MPK38.