Emerging evidence suggests that AT-Rich Interaction Domain 5b (Arid5b) may play a role in energy metabolism in various tissues. To study the metabolic function of Arid5b in skeletal muscle, we generated skeletal muscle-specific Arid5b knockout (Arid5b MKO) mice. We found that Arid5b MKO skeletal muscles preferentially utilized fatty acids for energy generation with a corresponding increase in FABP4 expression. Interestingly, in Arid5b MKO mice, the adipose tissue weight decreased significantly. One possible mechanism for the decrease in adipose tissue weight could be the increase in phospho-HSL and HSL expression in white adipose tissue. While glucose uptake increased in an insulin-independent manner in Arid5b MKO skeletal muscle, glucose oxidation was reduced in conjunction with downregulation of the mitochondrial pyruvate carrier (MPC). We found that glucose was diverted into the pentose phosphate pathway as well as converted into lactate through glycolysis for export to the bloodstream, fueling the Cori cycle. Our data show that muscle-specific deletion of Arid5b leads to changes in fuel utilization in skeletal muscle that influences metabolism in other tissues. These results suggest that Arid5b regulates systemic metabolism by modulating fuel selection.

During B cell development in bone marrow, large precursor B cells (large Pre-B cells) proliferate rapidly, exit the cell cycle, and differentiate into non-proliferative (quiescent) small Pre-B cells. Dysregulation of this process may result in the failure to produce functional B cells and pose a risk of leukemic transformation. Here, we report that AT rich interacting domain 5B (ARID5B), a B cell acute lymphoblastic leukemia (B-ALL) risk gene, regulates B cell development at the Pre-B stage. In both mice and humans, we observed a significant upregulation of ARID5B expression that initiates at the Pre-B stage and is maintained throughout later stages of B cell development. In mice, deletion of Arid5b in vivo and ex vivo exhibited a significant reduction in the proportion of immature B cells but an increase in large and small Pre-B cells. Arid5b inhibition ex vivo also led to an increase in proliferation of both Pre-B cell populations. Metabolic studies in mouse and human bone marrow revealed that fatty acid uptake peaked in proliferative B cells then decreased during non-proliferative stages. We showed that Arid5b ablation enhanced fatty acid uptake and oxidation in Pre-B cells. Furthermore, decreased ARID5B expression was observed in tumor cells from B-ALL patients when compared to B cells from non-leukemic individuals. In B-ALL patients, ARID5B expression below the median was associated with decreased survival particularly in subtypes originating from Pre-B cells. Collectively, our data indicated that Arid5b regulates fatty acid metabolism and proliferation of Pre-B cells in mice, and reduced expression of ARID5B in humans is a risk factor for B cell leukemia.

Background Skeletal muscle has an important role in regulating whole-body energy homeostasis, and energy production depends on the efficient function of mitochondria. We demonstrated previously that AT-rich interactive domain 5b (Arid5b) knockout (Arid5b(-/-)) mice were lean and resistant to high-fat diet (HFD)-induced obesity. While a potential role ofArid5bin energy metabolism has been suggested in adipocytes and hepatocytes, the role ofArid5bin skeletal muscle metabolism has not been studied. Therefore, we investigated whether energy metabolism is altered inArid5b(-/-)skeletal muscle. Results Arid5b(-/-)skeletal muscles showed increased basal glucose uptake, glycogen content, glucose oxidation and ATP content. Additionally, glucose clearance and oxygen consumption were upregulated inArid5b(-/-)mice. The expression of glucose transporter 1 (GLUT1) and 4 (GLUT4) in the gastrocnemius (GC) muscle remained unchanged. Intriguingly, the expression of TBC domain family member 1 (TBC1D1), which negatively regulates GLUT4 translocation to the plasma membrane, was suppressed inArid5b(-/-)skeletal muscle. Coimmunofluorescence staining of the GC muscle sections for GLUT4 and dystrophin revealed increased GLUT4 localization at the plasma membrane inArid5b(-/-)muscle. Conclusions The current study showed that the knockout ofArid5benhanced glucose metabolism through the downregulation of TBC1D1 and increased GLUT4 membrane translocation in skeletal muscle.

Background: Adipose tissue considerably influence metabolic homeostasis and play a central role in regulating whole-body energy and glucose metabolism. Previously, we have reported that mice with the global deletion of Arid5b are lean and have less fat in white and brown adipose tissues. However, this role is unknown in adipocyte specific Arid5b knockout (5bFKO) mice. Aim: We investigated the effects of adipose-specific deficiency of Arid5b on systemic glucose homeostasis and adipose tissue metabolism. Result: Deletion of Arid5b in adipose tissue using adiponectin promoter-driven Cre recombinase significantly improved glucose tolerance with significant reduction of insulin level. Body weight of 5bFKO mice was significantly reduced at the later age. Core body temperature of 5bFKO mice was significantly higher compared to the control mice. Robust increase in the protein expression of uncoupling protein 1 (Ucp1) was observed in inguinal white adipose tissue (iWAT) of 5bFKO mice housed at ambient temperature. This phenotype was further confirmed by prolonged cold exposure where Ucp1 and mitochondrial proteins such as pyruvate dehydrogenase (PDH), mitochondrially encoded cytochrome c oxidase (MTCO1) and ATP5A were substantially increased in iWAT of adipocyte specific Arid5b deficient mice. Gene expression of beige adipogenesis markers such as cell death inducing DFFA like effector A (Cidea) and iodothyronine deiodinase 2 (Dio2) were also significantly increased indicating browning of iWAT. Furthermore, loss of Arid5B in fat led to significant reduction in macrophages and total immune cells in iWAT. All together these results show that the deletion of Arid5b could promote browning of iWAT. Conclusion: These findings demonstrate that Arid5b regulates thermogenic genes expression to promote beige adipocytes formation and controls adipose inflammation. Inhibition of Arid5b may provide a novel therapeutic approach for obesity and diabetes. Disclosure M. Shukare: None. R. Huang: None. A. Ehsani: None. G. Zhang: None. J. Chalise: None. R. H. Whitson: None. K. Itakura: None.