The mechanisms underlying enhanced insulin-induced de novo lipogenesis (DNL) in an insulin resistant liver are not understood. Genetic studies in subjects with inherited metabolic syndrome, a cluster of phenotypes that includes dyslipidemia, glucose intolerance, central obesity and insulin resistance led to the identification of perfectly segregating mutations in the Dyrk1b gene. This work also revealed previously unknown function of Dyrk1b in glucose and lipid metabolism. In this study, we introduce Dyrk1b as the missing link between enhanced HGP and increased DNL. The liver specific Dyrk1b knockdown protected against hepatic steatosis, hyperlipidemia and diet induced insulin resistance, while AAV mediated Dyrk1b elevation enhanced DNL causing hepatic steatosis, hyperlipidemia and augmented hepatic Glucose Production (HGP), features characteristic of diabetic dyslipidemia. A comprehensive analysis revealed that Dyrk1b facilitates DNL by binding and activating the mTORC2 complex in a kinase independent fashion. Mechanistically, Dyrk1b displaces mTORC2 inhibitor Fkbp12 from the complex and induces auto-phosphorylation of the mTOR protein. Accordingly, the knockout of mTORC2 function, rescued hepatic steatosis, inflammation, and hyperlipidemia. The global relevance of this disease pathway is illustrated by increased hepatic Dyrk1b levels in mice and humans with hepatic steatosis. Altogether, our findings reveal Dyrk1b as a nutrient sensing protein that triggers DNL and hepatic insulin resistance and is an attractive therapeutic target for type 2 diabetes.


N. Bhat: None.


National Institutes of Health (RHL135767A, P30DK034989)

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