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Functional Expression of MT2 (Mel1b) Melatonin Receptors in Human PAZ6 Adipocytes

Centre National de la Recherche Scientifique-UPR 0415 and Université Paris VII, Institut Cochin de Génétique Moléculaire (L.B., L.P., A.D.S., R.J.), F-75014 Paris, France; Rowett Research Institute (L.B.), Bucksburn, Aberdeen, United Kingdom AB2 9SB; and Institut de Recherches Internationales Servier (P.D.), F-92415 Courbevoie, France

Address all correspondence and requests for reprints to: Dr. Ralf Jockers, Centre National de la Recherche Scientifique, UPR415, Institut Cochin de Génétique Moléculaire, 22 rue Méchain, F-75014 Paris, France. E-mail: jockers{at}cochin.inserm.fr

Several reports have demonstrated that the pineal hormone, melatonin, plays an important role in body mass regulation in mammals. To date, however, the target tissues and relevant biochemical mechanisms involved remain uncharacterized. As adipose tissue is the principal site of energy storage in the body, we investigated whether melatonin could also act on this tissue. Semiquantitative RT-PCR analysis revealed the expression of MT1 and MT2 melatonin receptor mRNAs in the human brown adipose cell line, PAZ6, as well as in human brown and white adipose tissue. Binding analysis with 2-[¹²⁵I]iodomelatonin (¹²⁵I-Mel) revealed the presence of a single, high affinity binding site in PAZ6 adipocytes with a binding capacity of 7.46 ± 1.58 fmol/mg protein and a K_d of 457 ± 5 pM. Both melatonin and the MT2 receptor-selective antagonist, 4-phenyl-2-propionamidotetraline, competed with 2-[¹²⁵I]iodomelatonin binding, with respective K_i values of 3 x 10^-11 and 1.5 x 10^-11 M. Functional expression of melatonin receptors in PAZ6 adipocytes was indicated by the melatonin-induced, dose-dependent inhibition of forskolin-stimulated cAMP levels and basal cGMP levels with IC₅₀ values of 2 x 10^-9 and 3 x 10^-10 M, respectively. Modulation of the cGMP pathway by melatonin further supports functional expression of MT2 receptors, as this pathway was shown to be specific for that subtype in humans. In addition, long-term melatonin treatment of PAZ6 adipocytes was found to decrease the expression of the glucose transporter Glut4 and glucose uptake, an important parameter of adipocyte metabolism. These results suggest that melatonin may act directly at MT2 receptors on human brown adipocytes to regulate adipocyte physiology.

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