The liver plays a central role in maintaining metabolic flexibility by regulating signaling pathways. Disruption in this process can lead to metabolic disease, such as obesity and cardiovascular risk. Scaffold proteins are well known to coordinate many signaling cascades. Since IQ Motif Containing GTPase Activating Protein 2 (IQGAP2) is a highly expressed scaffold protein in the liver, we examined its role in regulating metabolic programs. Adult wild type and Iqgap2−/− mice were fed ad libitum or fasted for 24 hours (9.00 am, or ZT4) and both male and female mice were used in this study to determine for sex differences in metabolism. We examined their gross morphology, performed serum biochemical assays and quantified expression of key enzymes regulating metabolic pathways including fat and carbohydrates. We found deficiency of IQGAP2 did not alter gross morphological features, liver‐to‐body weight ratio or white adipose tissue (WAT) weight. Iqgap2−/− male mice did not show pronounced differences in metabolic gene expression or fuel accumulation. In contrast, Iqgap2−/− female mice showed decreased expression of gluconeogenic, ketogenic and fatty acid oxidation genes. This basal decrease was compensated upon fasting with higher induction of ketogenic and gluconeogenic programs in Iqgap2−/− female mice. Our preliminary data suggest female Iqgap2−/− mice have defective nutrient storage. The two main hepatic fuel stores are glycogen and triglycerides. While hepatic triglycerides were not altered in female Iqgap2−/− mice, glycogen accumulation was significantly reduced. Histological analysis of hepatic glycogen accumulation showed distinct pericentral zonation which was apparent in the fed state. Consistent with this result, female Iqgap2−/− livers displayed reduced expression of genes regulating glycogen synthesis and degradation. Taken together, these data suggest a novel role for IQGAP2 in regulating hepatic fuel storage, especially glycogen levels. Support or Funding Information Illinois Campus Research Board and American Cancer Society

Running title: IQGAP2 alters GSK3 activityKeywords: scaffold protein, glycogen synthase kinase 3 (GSK-3), beta-catenin (β-catenin), liver, carbohydrate and lipid metabolism AbstractThe liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes of fats, proteins, and carbohydrates. The IQ motif containing GTPase activating protein 2 (IQGAP2) is a member of the IQGAP family. Of the three homologous isoforms, the IQGAP2 scaffolding protein is predominantly found in the liver. To characterize its role in regulating metabolism, Iqgap2 -/female and male mice, and their WT controls, were fed ad libitum or fasted for 24 hours. Hepatic gene expression, protein levels, and the metabolic response were compared between WT and Iqgap2 -/mice, using RT-qPCR, western blot analysis, and histological stains. We found that loss of IQGAP2 alters the phosphorylation of active glycogen synthase kinase 3 (GSK3) expression, a known regulator of glycogen synthesis and lipogenesis. Consistent with this result, Iqgap2 -/female mice displayed depletion of periportal glycogen even in the fed state. We also observed the blunted expression of genes involved in glycogenesis and lipogenesis when IQGAP2 was deleted. Since GSK3 is known to regulate the activity of β-catenin, we examined and found it to be reduced in Iqgap2 -/mice. Our findings demonstrate that IQGAP2 plays an important role in regulating glycogen synthesis.