Journal of Korean Endocrine Society 1999;14(1):14-17.
Published online January 1, 2001.
Leptin and Diabetes Mellitus.
Yong Sung Kim
Leptin secreted from adipose tissue activates not only its receptors expressed abundantly in the brain, including arcuate nucleus but the POMC neurons resulting in secretion of a-MSH. Activation of MC4R by a-MSH increases the energy expenditure and decreases the food intake, and promotes the sympathetic activity. METHODS: To analyze the biologic activity of a-MSH analogues, the rat MC3R DNA and human MC4R DNA were stably and independently expressed in CHO cell lines, and we performed the competitive receptor binding assay with [125I]NDP-MSH as a radioligand and cyclic AMP accumulation assay following treatment with different ligands. a-MSH (Ac-Ser-Tyr-Ser- Met-Glue-His-Phe-Arg-Trp-Gly-Lys-Val-NH2) and its analogue a-MSH-ND (Ac-Nle-Asp-His-Dphe- Arg-Trp-Lys-NH2) were synthesized by Genosys Biotechnologies, Inc. The HPLC purified samples for NMR experiments were dissolved in 90% HO/10% DO or 99.9% DO solutions at pH 7.0 with concentrations of 2 mM in 50 mM sodium phosphate buffer. The NMR spectra were acquired on a Bruker AMX-500 or DMX-600 spectrometer in quadrature detection mode equipped with a triple-resonance probe with an actively shielded pulsed field gradient coil. RESULTS: The preferential order of binding activity for MC3R was NDP-MSH > a-MSH-ND > [Nle4]-MSH with IC50 values (nM) being 0.367 +/- 0.074, 47.20 +/- 9.08 and 106.70 +/- 32.25, respectively. For MC4R, the same preferential order, NDP-MSH (0.566 +/- 0.194) > a-MSH-ND (6.70 +/- 1.07) > [Nle4]a-MSH (238.30 +/- 30.47), were obtained. In c-AMP generation assay, the potency order of peptides was NDP-MSH > a-MSH-ND > a-MSH at both MC3R and MCAR. Accumulated food intake of Sprague Dawley rats was low significantly for six hours after injection of a-MSH-ND into peritoneum. a-MSH forms a hair pin loop conformation, whereas a-MSH-ND, a linear form of MTII, prefers a type I B-turn comprising residues Asp5-His6-DPhe7-Arg8 in NMR study. CONCLUSION: we developed in vitro and in vivo bioassay system to evaluate the biologic activity of a-MSH analogues and we also showed that the type I B-turn structure of a-MSH-ND might enhance the binding activity to MC4R.

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