@article {Frabutt849000, author = {Dylan Frabutt and Natalie Stull and Annie R. Pineros and Sarah A. Tersey and Donalyn Scheuner and Teresa L. Mastracci and Michael J. Pugia}, title = {Adiponectin Receptor Fragmentation in Mouse Models of Type 1 and Type 2 Diabetes}, elocation-id = {849000}, year = {2019}, doi = {10.1101/849000}, publisher = {Cold Spring Harbor Laboratory}, abstract = {The protein hormone adiponectin regulates glucose and fatty acid metabolism by binding to two PAQR-family receptors (AdipoR1 and AdipoR2). Both receptors feature a C-terminal segment which is released by proteolysis to form a freely-circulating C-terminal fragment (CTF) found in the plasma of normal individuals but not in some undefined diabetes patients. The AdipoR1-CTF344-376 is a competitive inhibitor of tumor necrosis factor α cleavage enzyme (TACE) but it contains a shorter peptide domain (AdipoR1 CTF351-362) that is a strong non-competitive inhibitor of insulin-degrading enzyme (IDE). The link between adiponectin receptor fragmentation and diabetes pathology is unclear but could lead to new therapeutic strategies. We therefore investigated physiological variations in the concentrations of CTF in non-obese diabetic (NOD/ShiLtJ) mice and C57BL/6 mice with diet-induced obesity (DIO) as models of diabetes types 1 and 2, respectively. We tested for changes in adiponectin receptor signaling, immune responses, disease progression, and the abundance of neutralizing autoantibodies. Finally, we administered exogenous AdipoR1-CTF peptides either containing or lacking the IDE-binding domain. We observed the more pronounced CTF shedding in the TACE-active NOD mice, which represents an inflammatory autoimmune phenotype, but fragmentation was also observed to a lesser extent in the DIO model. Autoantibodies to CTF were detected in both models. Neither exogenous CTF peptide affected IgG-CTF plasma levels, body weight or the conversion of NOD mice to diabetes. The pattern of AdipoR1 fragmentation and autoantibody production under physiological conditions of aging, DIO, and autoimmune diabetes therefore provides insight into the association adiponectin biology and diabetes.ACCAcetyl coenzyme A carboxylaseAKTProtein kinase BAMPK5{\textquoteright}-AMP-activated protein kinaseCTFC-terminal fragment of the adiponectin receptor GLUT Glucose transporterGTTGlucose tolerance testIDEInsulin degradation enzymeITTInsulin tolerance testIPIntraperitonealMAPKMitogen-activated protein kinasePPARPeroxisome proliferator-activated receptor T1D Type 1 diabetesT2DType 2 diabetesTACETumor necrosis factor-α cleavage enzyme (aka ADAM-17, MMP-17)TNFαTumor necrosis factor-α}, URL = {https://www.biorxiv.org/content/early/2019/11/20/849000}, eprint = {https://www.biorxiv.org/content/early/2019/11/20/849000.full.pdf}, journal = {bioRxiv} }