title: 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.
abstract: 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.
authors.affiliation: Tupper Research Institute, Department of Medicine, Division of Endocrinology, New England Medical Center, Boston, Massachusetts 02111, USA.
authors.forename: C
authors.initials: C
authors.lastname: Fekete
authors.forename: G
authors.initials: G
authors.lastname: Légrádi
authors.forename: E
authors.initials: E
authors.lastname: Mihály
authors.forename: Q H
authors.initials: QH
authors.lastname: Huang
authors.forename: J B
authors.initials: JB
authors.lastname: Tatro
authors.forename: W M
authors.initials: WM
authors.lastname: Rand
authors.forename: C H
authors.initials: CH
authors.lastname: Emerson
authors.forename: R M
authors.initials: RM
authors.lastname: Lechan
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005215:Fasting / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D016253:Microscopy, Immunoelectron; D009411:Nerve Endings / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D013972:Thyrotropin / Q000097:blood; D013973:Thyrotropin-Releasing Hormone / Q000032:analysis / Q000235:genetics*; D013974:Thyroxine / Q000097:blood; D000521:alpha-MSH / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*
chemical_list: D011498:Protein Precursors; D000521:alpha-MSH; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; C046418:pro-thyrotropin releasing hormone; D013974:Thyroxine; D011761:Pyrrolidonecarboxylic Acid