Protein kinase Cβ activates fat mass and obesity‐associated protein by influencing its ubiquitin/proteasome degradation

ABSTRACT Protein kinase Cβ (PKCβ) is a serine‐threonine kinase associated with obesity and diabetic complications; its activation contributes to weight gain, and deletion of its gene results in resistance to genetic‐ and diet‐induced obesity. Fat mass and obesity‐associated (FTO) protein is a recently identified RNA demethylase, and its overexpression in mice leads to increased body weight as well as fat mass. Although sharing some features in anabolism regulation, PKCβ and FTO have not been investigated together; therefore, their relationship has not been established. We report that PKCβ positively regulates FTO on the posttranslation level, evidenced by the facts that PKCβ activation contributes to high‐glucose‐induced FTO up‐regulation, and overexpression of PKCβ suppresses ubiquitin‐proteasome degradation of FTO, whereas PKCβ inactivation acts in the opposite manner. It was also found that PKCβ can phosphorylate FTO on threonine, and this phosphorylation requires both catalytic and regulatory domains of PKCβ. Moreover, PKCβ inhibition can suppress 3T3‐L1 cell differentiation in normal and FTO‐overexpressing cells but not in FTO‐silenced or ‐inhibited cells. We propose that PKCβ acts to suppress the degradation of FTO protein and reveals the associated role of PKCβ and FTO in adipogenesis, suggesting a new pathway that affects the development of obesity and metabolic diseases.—Tai, H., Wang, X., Zhou, J., Han, X., Fang, T., Gong, H., Huang, N., Chen, H., Qin, J., Yang, M., Wei, X., Yang, L., Xiao, H. Protein kinase Cβ activates fat mass and obesity‐associated protein by influencing its ubiquitin/proteasome degradation. FASEB J. 31, 4396–4406 (2017). www.fasebj.org