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Effect of Agouti-Related Protein in Regulation of the Hypothalamic-Pituitary-Thyroid Axis in the Melanocortin 4 Receptor Knockout Mouse

Tupper Research Institute and Department of Medicine (C.F., S.S., R.M.L.), Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts-New England Medical Center, and Departments of Community Health (W.M.R.) and Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111; Division of Endocrine Neurobiology (C.F.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 1083, Hungary; Department of Medicine, Division of Endocrinology (C.H.E.), University of Massachusetts Medical School, Worcester, Massachusetts 01655; and Vollum Institute, Oregon Health and Science University (R.D.C), Department of Pediatrics (D.L.M.), Center for the Study of Weight Regulation (D.L.M., R.D.C.), Portland Oregon 97239

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}tufts-nemc.org.

Agouti-related protein (AGRP) is thought to be one of the neuropeptides mediating the effects of leptin on appetite and satiety. The central administration of AGRP not only stimulates food intake, but also inhibits the hypothalamic-pituitary-thyroid axis (HPT) axis, closely replicating the central hypothyroid state induced by fasting. AGRP binds as an endogenous antagonist or inverse agonist of the central melanocortin receptors but has also been hypothesized to have melanocortin receptor-independent effects. Thus, we determined whether the central effects of AGRP on the HPT axis are altered in mice with selective deletion of the melanocortin 4 receptor (MC4-R). AGRP or artificial cerebrospinal fluid was administered daily into the lateral ventricle of adult, male MC4-R knockout and wild-type (WT) mice for 3 d. AGRP significantly increased the cumulative food intake and weight of white and brown adipose tissue, suppressed circulating levels of T₄ [control vs. AGRP in WT (µg/dl): 4.54 ± 0.16 vs. 3.87 ± 21], and inhibited proTRH mRNA content in the hypothalamic paraventricular nucleus of WT mice (control vs. AGRP in WT (density units ± SEM): 4.65 ± 0.50 vs. 2.47 ± 0.17). In contrast, no significant effects of AGRP were observed in any of these parameters in the MC4-R knockout mice. These data suggest that AGRP signaling to TRH hypophysiotropic neurons in the paraventricular nucleus is primarily mediated by the MC4-R and therefore, binding to the MC3-R or other putative AGRP receptors may have only a minor role.

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