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Department of Neurobiology (C.F.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary 1083; Tupper Research Institute and Department of Medicine (S.S., R.M.L.), Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts-New England Medical Center, Boston, Massachusetts 02111; Departments of Community Health (W.M.R.) and Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111; Thyroid Division (J.W.H., A.C.B.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Department of Medicine (C.H.E.), Division of Endocrinology, University of Massachusetts Medical School, Worcester, Massachusetts 01655
Address all correspondence and requests for reprints to: Ronald M. Lechan, M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Box No. 268, Tufts-New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. E-mail: rlechan{at}lifespan.org.
Because 
-MSH has a potent stimulatory action on hypophysiotropic TRH synthesizing neurons in the hypothalamic paraventricular nucleus (PVN), preventing the effects of fasting on the gene expression of the TRH prohormone (proTRH), we hypothesized that agouti-related protein (AGRP), a melanocortin receptor antagonist, may exert a central inhibitory action on these neurons. To test the hypothesis, the effects of intracerebroventricularly administered AGRP on circulating thyroid hormone levels and proTRH mRNA in the hypothalamic paraventricular nucleus (PVN) were compared with the effects of the recently described central inhibitor of the HPT axis, neuropeptide Y (NPY). AGRP administration increased food consumption and weight gain, suppressed circulating levels of thyroid hormones (T3 and T4), and resulted in an inappropriately normal TSH. These alterations were associated with a significant suppression of proTRH mRNA in the PVN, indicating that AGRP infusion resulted in a state of central hypothyroidism. While similar observations were made in the NPY-infused animals, AGRP-treated animals had higher feeding efficiency, higher T4 levels, and lower type 2 iodothyronine deiodinase levels in brown adipose tissue than NPY-infused animals. These data demonstrate that AGRP and NPY have a similarly potent inhibitory action on the proTRH gene expression of hypophysiotropic neurons, indicating that both AGRP and NPY may play a major role in the inhibition of the HPT axis during fasting.
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