alpha-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression

J Neurosci. 2000 Feb 15;20(4):1550-8. doi: 10.1523/JNEUROSCI.20-04-01550.2000.


The hypothalamic arcuate nucleus has an essential role in mediating the homeostatic responses of the thyroid axis to fasting by altering the sensitivity of prothyrotropin-releasing hormone (pro-TRH) gene expression in the paraventricular nucleus (PVN) to feedback regulation by thyroid hormone. Because agouti-related protein (AGRP), a leptin-regulated, arcuate nucleus-derived peptide with alpha-MSH antagonist activity, is contained in axon terminals that terminate on TRH neurons in the PVN, we raised the possibility that alpha-MSH may also participate in the mechanism by which leptin influences pro-TRH gene expression. By double-labeling immunocytochemistry, alpha-MSH-IR axon varicosities were juxtaposed to approximately 70% of pro-TRH neurons in the anterior and periventricular parvocellular subdivisions of the PVN and to 34% of pro-TRH neurons in the medial parvocellular subdivision, establishing synaptic contacts both on the cell soma and dendrites. All pro-TRH neurons receiving contacts by alpha-MSH-containing fibers also were innervated by axons containing AGRP. The intracerebroventricular infusion of 300 ng of alpha-MSH every 6 hr for 3 d prevented fasting-induced suppression of pro-TRH in the PVN but had no effect on AGRP mRNA in the arcuate nucleus. alpha-MSH also increased circulating levels of free thyroxine (T4) 2.5-fold over the levels in fasted controls, but free T4 did not reach the levels in fed controls. These data suggest that alpha-MSH has an important role in the activation of pro-TRH gene expression in hypophysiotropic neurons via either a mono- and/or multisynaptic pathway to the PVN, but factors in addition to alpha-MSH also contribute to the mechanism by which leptin administration restores thyroid hormone levels to normal in fasted animals.

Publication types

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

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Fasting / physiology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Microscopy, Immunoelectron
  • Nerve Endings / physiology*
  • Nerve Endings / ultrastructure
  • Neurons / cytology
  • Neurons / physiology*
  • Neurons / ultrastructure
  • Paraventricular Hypothalamic Nucleus / cytology
  • Paraventricular Hypothalamic Nucleus / physiology*
  • Paraventricular Hypothalamic Nucleus / ultrastructure
  • Protein Precursors / analysis
  • Protein Precursors / genetics*
  • Pyrrolidonecarboxylic Acid / analogs & derivatives
  • Rats
  • Rats, Sprague-Dawley
  • Thyrotropin / blood
  • Thyrotropin-Releasing Hormone / analysis
  • Thyrotropin-Releasing Hormone / genetics*
  • Thyroxine / blood
  • alpha-MSH / analysis
  • alpha-MSH / pharmacology
  • alpha-MSH / physiology*


  • Protein Precursors
  • alpha-MSH
  • Thyrotropin-Releasing Hormone
  • Thyrotropin
  • pro-thyrotropin releasing hormone
  • Thyroxine
  • Pyrrolidonecarboxylic Acid