Abstract
Adiponectin is a fat tissue-derived adipokine with beneficial effects against diabetes, cardiovascular diseases, and cancer. Accordingly, adiponectin-mimetic molecules possess significant pharmacological potential. Oligomeric states of adiponectin appear to determine its biological activity. We identified a highly conserved, 13-residue segment (ADP-1) from adiponectin's collagen domain, which comprises GXXG motifs and has one asparagine and two histidine residues that assist in oligomeric protein assembly. We therefore hypothesized that ADP-1 promotes oligomeric assembly and thereby mediates potential metabolic effects. We observed here that ADP-1 is stable in human serum and oligomerizes in aqueous environments. We also found that ADP-1 activates AMP-activated protein kinase (AMPK) in an adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)-dependent pathway and stimulates glucose uptake in rat skeletal muscle cells (L6 myotubes). ADP-1-induced glucose transport coincided with ADP-1-induced biosynthesis of glucose transporter 4 and its translocation to the plasma membrane. ADP-1 induced an interaction between APPL1 and the small GTPase Rab5, resulting in AMPK phosphorylation, in turn leading to phosphorylation of p38 mitogen-activated protein kinase (MAPK), acetyl-CoA carboxylase, and peroxisome proliferator-activated receptor α. Similar to adiponectin, ADP-1 increased the expression of the adiponectin receptor 1 (AdipoR1) gene. Of note, ADP-1 decreased blood glucose levels and enhanced insulin production in pancreatic β cells in db/db mice. Further, ADP-1 beneficially affected lipid metabolism by enhancing lipid globule formation in mouse 3T3-L1 adipocytes. To our knowledge, this is the first report on identification of a short peptide from adiponectin with positive effects on glucose or fatty acid metabolism.
Highlights
Adiponectin is a fat tissue– derived adipokine with beneficial effects against diabetes, cardiovascular diseases, and cancer
We found that ADP-1 activates AMP-activated protein kinase (AMPK) in an adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)-dependent pathway and stimulates glucose uptake in rat skeletal muscle cells (L6 myotubes)
ADP-1 induced an interaction between APPL1 and the small GTPase Rab5, resulting in AMPK phosphorylation, in turn leading to phosphorylation of p38 mitogen-activated protein kinase (MAPK), acetyl-CoA carboxylase, and peroxisome proliferator–activated receptor ␣
Summary
A collagen domain– derived short adiponectin peptide activates APPL1 and AMPK signaling pathways and improves glucose and fatty acid metabolisms. Because osteoblast differentiation and type 2 diabetes are closely associated with respect to biochemical pathways/molecular mechanisms [21,22,23,24], we hypothesized that it would be worthwhile to explore a peptide with metabolic effects of adiponectin from its collagen domain. Toward this end, we have identified a region corresponding to amino acid residues 42–54 from the collagen domain of adiponectin that possesses the amino acids and structural motif for oligomeric assembly. Our detailed characterization with in vitro studies in rat skeletal muscle cells (L6 myotubes), ex vivo studies in primary skeletal muscle cells of db/db mice, and in vivo experiments in db/db mice revealed a strong metabolic effect of this 13-residue collagen domain– derived peptide
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
