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 C-peptide, 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.

中文翻译：

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纳摩尔大环黑皮质素受体激动剂 MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro]) 的比较脑室内和鞘内给药减少小鼠的食物摄入。

迫切需要找到安全的疗法来治疗日益肥胖的人群和与能量稳态失衡相关的疾病。黑皮质素 3 受体 (MC3R) 和黑皮质素 4 受体 (MC4R) 配体长期以来一直是帮助科学家了解能量稳态和摄食行为调节的焦点。在此，我们使用纳摩尔大环黑皮质素受体激动剂配体 MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro) 来检查鞘内 (IT) 直接给药后的代谢和能量止血情况。与直接进入大脑的脑室内 (ICV) 给药相比，脊髓。总体而言，MDE6-5-2c 的中央 ICV 给药导致食物摄入量减少，呈剂量依赖性，并降低呼吸交换比 (RER)。MDE6-5-2c 给药的 IT 与 ICV 途径的比较导致 MDE6-5-2c 通过 IT 对喂养行为和 RER 具有更长的作用持续时间。使用 IT 与 ICV MDE6-5-2c 给药途径比较 C 肽、生长素释放肽、GIP、瘦素、IL-6 和抵抗素血浆激素和生物标志物。与 ICV 载体对照治疗相比，MDE6-5-2c 的 ICV 治疗后血浆抵抗素水平降低。与 ICV 给药相比，鞘内治疗导致炎性细胞因子白细胞介素 6 (IL-6) 水平显着降低。对非选择性 MC3R 和 MC4R 大环激动剂 MDE6-5-2c 分子的研究揭示了食物摄入量、RER、体内。