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      Regulation of Hypothalamic Proopiomelanocortin by Leptin in Lean and Obese Rats

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          The mechanisms by which leptin influences energy homeostasis are not entirely understood. Several observations indicate that proopiomelanocortin (POMC) is involved in the regulation of food intake and may be a mediator of leptin action. To further study this interaction, a sensitive solution hybridization assay was used to compare the levels of POMC mRNA in the medial basal hypothalamus (MBH) of lean (+/+, +/ fa<sup>f</sup>) and obese leptin receptor-deficient (fa<sup>f</sup>/fa<sup>f</sup>) rats. POMC peptide products were also measured by RIA in the same animals. Cytoplasmic POMC RNA levels were significantly reduced by 53% in obese rats as compared with lean controls: 0.30 ± 0.04 vs. 0.64 ± 0.07 pg/µg total RNA (p < 0.02). Significant reductions in mean concentrations of hypothalamic POMC-derived peptides from the same dissections were detected in the obese rats vs. lean controls: α-MSH 1.77 ± 0.07 vs. 2.34 ± 0.10; β-EP 4.06 ± 0.24 vs. 5.86 ± 0.36; γ<sub>3</sub>-MSH 5.32 ± 0.20 vs. 6.52 ± 0.12 ng/mg protein (p < 0.001). To determine whether leptin stimulates POMC gene transcription, the acute effect of an intracerebroventricular (i.c.v.) injection of leptin (5 µg) on POMC primary transcript was quantified in the MBH of lean rats after a 16-hour fast. There was a significant 167% increase in mean POMC hnRNA levels 3 h after i.c.v. leptin injection (1.15 ± 0.22 pg/MBH; p < 0.02), but not after 1 h (0.76 ± 0.08 pg/MBH), compared to saline controls (0.69 ± 0.08 pg/MBH). 4 h after the injection of leptin, POMC hnRNA was still increased, but to a lesser extent (140%), as compared with control animals (p = 0.006). These studies demonstrate for the first time in the leptin receptor-deficient rat that there is an associated decrease in POMC gene expression and peptide levels in the MBH. Furthermore, the acute increase in the levels of POMC primary transcript in non-obese rats after a single i.c.v. injection of leptin supports a role for leptin in the regulation of POMC gene transcription. Taken together, these studies provide further evidence that POMC is an important mediator of the effects of leptin on food intake and energy expenditure.

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          Most cited references 9

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          Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor.

          The genetic loci agouti and extension control the relative amounts of eumelanin (brown-black) and phaeomelanin (yellow-red) pigments in mammals: extension encodes the receptor for melanocyte-stimulating hormone (MSH) and agouti encodes a novel 131-amino-acid protein containing a signal sequence. Agouti, which is produced in the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur. Here we use partially purified agouti protein to demonstrate that agouti is a high-affinity antagonist of the MSH receptor and blocks alpha-MSH stimulation of adenylyl cyclase, the effector through which alpha-MSH induces eumelanin synthesis. Agouti was also found to be an antagonist of the melanocortin-4 receptor, a related MSH-binding receptor. Consequently, the obesity caused by ectopic expression of agouti in the lethal yellow (Ay) mouse may be due to the inhibition of melanocortin receptor(s) outside the hair follicle.
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            Design and synthesis of multi-haem proteins.

            A water-soluble, 62-residue, di-alpha-helical peptide has been synthesized which accommodates two bis-histidyl haem groups. The peptide assembles into a four-helix dimer with 2-fold symmetry and four parallel haems that closely resemble native haems in their spectral and electrochemical properties, including haem-haem redox interaction. This protein is an essential intermediate in the synthesis of molecular 'maquettes', a novel class of simplified versions of the metalloproteins involved in redox catalysis and in energy conversion in respiratory and photosynthetic electron transfer.
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              Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein


                Author and article information

                S. Karger AG
                December 1999
                24 December 1999
                : 70
                : 6
                : 377-383
                Departments of aMedicine and bPediatrics, Columbia University College of Physicians& Surgeons, New York, N.Y., and cDepartment of Biology, Vassar College, Poughkeepsie,N.Y., USA
                54499 Neuroendocrinology 1999;70:377–383
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 45, Pages: 7
                Regulation of Hypothalamic Neurons


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