Comparative intracerebroventricular and intrathecal administration of a nanomolar macrocyclic melanocortin receptor agonist MDE6- 5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro]) decreases food intake in mice

Carrie Haskell-Luevano, Danielle N. Adank, Mary M. Lunzer, Mark D. Ericson, Zoe M. Koeperich, Stacey L. Wilber, Katlyn A. Fleming

Research output: Contribution to journalArticlepeer-review

Abstract

There is a critical need to find safe therapeutics to treat an increasingly obese population and diseases associated with an imbalance in energy homeostasis. The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) ligands have long been the focus to help scientists understand energy homeostasis and the regulation of feeding behavior. Herein, we use a nanomolar macrocyclic melanocortin receptor agonist ligand MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro) to examine metabolic and energy hemostasis profiles upon intrathecal (IT) administration directly into the spinal cord as compared to intracerebroventricular (ICV) administration directly into the brain. Overall, central ICV administration of MDE6-5-2c resulted in decreased food intake, in a dose-dependent manner, and decreased respiratory exchange ratio (RER). Comparison of IT versus ICV routes of MDE6-5-2c administration resulted in MDE6-5-2c possessing a longer duration of action on both feeding behavior and RER via IT. The Cpeptide, ghrelin, GIP, leptin, IL-6, and resistin plasma hormones and biomarkers were compared using IT versus ICV MDE6-5-2c routes of administration. Plasma resistin levels were decreased upon ICV treatment of MDE6-5-2c, as compared to ICV vehicle control treatment. Intrathecal treatment resulted in significantly decreased inflammatory cytokine interleukin-6 (IL-6) levels compared to ICV administration. Investigation of the nonselective MC3R and MC4R macrocyclic agonist MDE6-5-2c molecule revealed differences in food intake, RER, and plasma biomarker profiles based upon ICV or IT routes of administration and characterize this novel molecular chemotype as a molecular probe to study the melanocortin system in vivo.

Original languageEnglish (US)
Pages (from-to)3051-3063
Number of pages13
JournalACS Chemical Neuroscience
Volume11
Issue number19
DOIs
StatePublished - Oct 7 2020

Bibliographical note

Funding Information:
These experiments were funded by the National Institute of Health through R01DK091906 (C.H.-L.) and the F32DK108Y02 Postdoctoral Fellowship (M.D.E).

Publisher Copyright:
© 2020 American Chemical Society.

Keywords

  • Feeding
  • ICV
  • IT
  • MC4R
  • Melanocortin
  • Obesity
  • TSE Cages

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Fingerprint

Dive into the research topics of 'Comparative intracerebroventricular and intrathecal administration of a nanomolar macrocyclic melanocortin receptor agonist MDE6- 5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro]) decreases food intake in mice'. Together they form a unique fingerprint.

Cite this