Starch binding domain-containing protein 1 (STBD1) is an endoplasmic reticulum (ER)-resident, glycogen-binding protein. In addition to glycogen, STBD1 has been shown to interact with several proteins implicated in glycogen synthesis and degradation, yet its function in glycogen metabolism remains largely unknown. In addition to the bulk of the ER, STBD1 has been reported to localize at regions of physical contact between mitochondria and the ER, known as Mitochondria-ER Contact sites (MERCs). Given the emerging correlation between distortions in the integrity of hepatic MERCs and insulin resistance, our study aimed to delineate the role of STBD1 in vivo by addressing potential abnormalities in glucose metabolism and ER-mitochondria communication associated with insulin resistance in mice with targeted inactivation of Stbd1 (Stbd1KO). We show that Stbd1KO mice at the age of 24 weeks displayed reduced hepatic glycogen content and aberrant control of glucose homeostasis, compatible with insulin resistance. In line with the above, Stbd1-deficient mice presented with increased fasting blood glucose and insulin levels, attenuated activation of insulin signaling in the liver and skeletal muscle and elevated liver sphingomyelin content, in the absence of hepatic steatosis. Furthermore, Stbd1KO mice were found to exhibit enhanced ER-mitochondria association and increased mitochondrial fragmentation in the liver. Nevertheless, the enzymatic activity of hepatic respiratory chain complexes and ER stress levels in the liver were not altered. Our findings identify a novel important role for STBD1 in the control of glucose metabolism, associated with the integrity of hepatic MERCs.
