Hypophysiotropic thyrotropin-releasing hormone-synthesizing neurons in the human hypothalamus are innervated by neuropeptide Y, agouti-related protein, and alpha-melanocyte-stimulating hormone

J Clin Endocrinol Metab. 2000 Jul;85(7):2596-603. doi: 10.1210/jcem.85.7.6662.


We recently demonstrated that three arcuate nucleus-derived peptides, neuropeptide Y (NPY), agouti-related protein (AGRP), and alphaMSH, 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, alphaMSH, and TRH in adult hypothalami obtained within 15 h of death. Numerous small to medium-sized, fusiform and multipolar NPY-, AGRP-, and alphaMSH-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 alphaMSH-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 alphaMSH- and AGRP-IR neurons. NPY-, AGRP-, and alphaMSH-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 alphaMSH-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Agouti-Related Protein
  • Female
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • Hypothalamus / cytology
  • Hypothalamus / metabolism*
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Nerve Fibers / metabolism
  • Neurons / metabolism*
  • Neuropeptide Y / physiology*
  • Paraventricular Hypothalamic Nucleus / cytology
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Paraventricular Hypothalamic Nucleus / physiology
  • Proteins / physiology*
  • Thyrotropin-Releasing Hormone / biosynthesis*
  • alpha-MSH / physiology*


  • AGRP protein, human
  • AGRP protein, rat
  • Agouti-Related Protein
  • Intercellular Signaling Peptides and Proteins
  • Neuropeptide Y
  • Proteins
  • alpha-MSH
  • Thyrotropin-Releasing Hormone