Stbd1 stimulates AMPK signaling and alleviates insulin resistance in an in vitro hepatocyte model

Starch‐binding domain‐containing protein 1 (Stbd1) is a glycogen‐binding protein which localizes to the endoplasmic reticulum (ER) membrane and ER‐mitochondria contact sites (ERMCs). The protein undergoes N ‐myristoylation, which is a major determinant of its subcellular targeting. Stbd1 has been implicated in the control of glucose homeostasis, as evidenced by the finding that mice with targeted inactivation of Stbd1 display insulin resistance associated with increased ERMCs in the liver. In the present study, we addressed the effects of increased Stbd1 expression levels on insulin signaling. We show that Stbd1 overexpression enhances cellular sensitivity to insulin and improves insulin resistance in an in vitro hepatocyte cell model. We further demonstrate that increased Stbd1 expression levels are associated with enhanced activation of the AMP‐activated protein kinase (AMPK), which is a central regulator of metabolism and an attractive therapeutic target for metabolic disorders related to insulin resistance, such as type 2 diabetes (T2D). The activation of AMPK signaling and the improved cellular response to insulin induced by Stbd1 overexpression occurred independently of N ‐myristoylation and associated changes in the number of ERMCs, glycogen levels, mitochondrial calcium, mitochondrial morphology, and respiratory function. Collectively, our findings uncover a new level of interaction between Stbd1 and AMPK, with Stbd1 acting as an upstream activator of AMPK signaling. Given that first‐line drug treatments for insulin resistance and T2D are known activators of the AMPK pathway, these findings may provide a new perspective for the development of more effective therapeutic strategies.