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Hypophysiotropic Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Human Hypothalamus Are Innervated by Neuropeptide Y, Agouti-Related Protein, and -Melanocyte-Stimulating Hormone¹

Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, New England Medical Center (E.M., C.F., J.B.T., R.M.L.), Boston, Massachusetts 02111; Department of Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences (C.F., Z.L.), 1083 Budapest, Hungary; Department of Pathology (Neuropathology Division), Brown University School of Medicine/Rhode Island Hospital (E.G.S.), Providence, Rhode Island 02903; and Department of Neuroscience, Tufts University School of Medicine (R.M.L.), Boston, Massachusetts 02111

Address all correspondence and requests for reprints to: Ronald M. Lechan, M.D., Ph.D., Division of Endocrinology, Box No. 268, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. E-mail: rlechan{at}lifespan.org

We recently demonstrated that three arcuate nucleus-derived peptides, neuropeptide Y (NPY), agouti-related protein (AGRP), and MSH, are contained in axon terminals that heavily innervate hypophysiotropic TRH neurons in the rat brain and may contribute to the altered set-point of the hypothalamo-pituitary-thyroid axis during fasting. To determine whether a similar regulatory system exists in human brain, we performed a series of immunohistochemical studies using antisera against NPY, AGRP, MSH, and TRH in adult hypothalami obtained within 15 h of death. Numerous small to medium-sized, fusiform and multipolar NPY-, AGRP-, and MSH-immunoreactive (-IR) cells were widely distributed throughout the rostro-caudal extent of the infundibular (arcuate) nucleus. A similar distribution pattern was found for NPY- and AGRP-IR neurons in the arcuate nucleus, whereas MSH-IR cells appeared to form a separate cell population. By double labeling fluorescent immunohistochemistry, 82% of NPY neurons cocontained AGRP, and 87% of AGRP neurons coexpressed NPY. No colocalization was found between MSH- and AGRP-IR neurons. NPY-, AGRP-, and MSH-containing axons densely innervated the hypothalamic paraventricular nucleus and were found in close juxtaposition to TRH-synthesizing cell bodies and dendrites. These studies demonstrate that in man, the NPY-, AGRP-, and MSH-IR neuronal systems in the infundibular and paraventricular nuclei are highly reminiscent of that observed in the rat and may similarly be involved in regulating the hypothalamo-pituitary-thyroid axis in the human brain.

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