The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including adiponectin. The research of adiponectin and its receptors is hampered owing to the difficulties in handling these proteins. The C-terminal half of adiponectin protein representing the globular domain (gAd) exhibits potent metabolic effects in various tissues. In addition, epidemiological studies found an inverse association between circulating adiponectin levels and several obesity-related malignancies, including cancers of the breast. In spite of the clinical need, before our studies adiponectin receptor response modifier peptides were not available.
Recently we developed and characterized a first-in-class adiponectin receptor agonist. This 10-amino acid residue multiply modified peptide has attractive physical properties and was indeed used to describe a series of cellular processes in vitro and investigate the potential of adiponectin-based therapies in vivo. Peptide ADP355 inhibits AdipoR-dependent cancer cell growth at 100 nM – 1 µM, frequently better than gAd. In scid mice carrying MCF-7 orthotopic xenografts, ADP355 treatment moderately reduces the growth of established tumors. Similarly modest effects were observed on preservation of body mass and fat pad weight in lipodystrophic mice suggesting that the structure needs further refinements to warrant further preclinical development efforts. Nevertheless, the peptide fully restores fear conditioning in lipodystrophic animals.
Based on the sequence of the AdipoR agonist, a novel receptor antagonist was designed according to general rules of agonist – antagonist conversions. This peptide counteracts 100 nM ADP355-mediated breast cancer cell growth inhibition in a concentration-dependent manner. The antagonist itself slightly promotes cell growth, perhaps due to antagonizing endogenous adiponectin or acting as an inverse agonist.