PEG-BHD1028 Peptide Regulates Insulin Resistance and Fatty Acid ?-Oxidation, and Mitochondrial Biogenesis by Binding to Two Heterogeneous Binding Sites of Adiponectin Receptors, AdipoR1 and AdipoR2.

ABSTRACT: Adiponectin plays multiple critical roles in modulating various physiological processes by binding to its receptors. The functions of PEG-BHD1028, a potent novel peptide agonist to AdipoRs, was evaluated using in vitro and in vivo models based on the reported action spectrum of adiponectin. To confirm the design concept of PEG-BHD1028, the binding sites and their affinities were analyzed using the SPR (Surface Plasmon Resonance) assay. The results revealed that PEG-BHD1028 was bound to two heterogeneous binding sites of AdipoR1 and AdipoR2 with a relatively high affinity. In C2C12 cells, PEG-BHD1028 significantly activated AMPK and subsequent pathways and enhanced fatty acid ?-oxidation and mitochondrial biogenesis. Furthermore, it also facilitated glucose uptake by lowering insulin resistance in insulin-resistant C2C12 cells. PEG-BHD1028 significantly reduced the fasting plasma glucose level in db/db mice following a single s.c. injection of 50, 100, and 200 ?g/Kg and glucose tolerance at a dose of 50 ?g/Kg with significantly decreased insulin production. The animals received 5, 25, and 50 ?g/Kg of PEG-BHD1028 for 21 days significantly lost their weight after 18 days in a range of 5-7%. These results imply the development of PEG-BHD1028 as a potential adiponectin replacement therapeutic agent.

SUBMITTER: Lee IK 

PROVIDER: S-EPMC7830917 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature