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Review
. 2010 Apr;31(2):134-56.
doi: 10.1016/j.yfrne.2010.01.001. Epub 2010 Jan 13.

Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs

Eduardo A Nillni  1
Affiliations
Review

Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs

Eduardo A Nillni. Front Neuroendocrinol. 2010 Apr.

Abstract

The hypothalamic-pituitary-thyroid (HPT) axis plays a critical role in mediating changes in metabolism and thermogenesis. Thus, the central regulation of the thyroid axis by Thyrotropin Releasing Hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) is of key importance for the normal function of the axis under different physiological conditions including cold stress and changes in nutritional status. Before the TRH peptide becomes biologically active, a series of tightly regulated processes occur including the proper folding of the prohormone for targeting to the secretory pathway, its post-translational processing, and targeting of the processed peptides to the secretory granules near the plasma membrane of the cell ready for secretion. Multiple inputs coming from the periphery or from neurons present in different areas of the brain including the hypothalamus are responsible for the activation or inhibition of the TRH neuron and in turn affect the output of TRH and the set point of the axis.

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Conflict of interest statement

Disclosure statement: The author has nothing to disclose

Figures

Figure 1
Figure 1. Schematic representation of the biosynthesis and post-translational processing of rat proTRH
A depicts the transcription and post-translational modifications in the rat proTRH composed of 231 amino acids. The signal sequence is cleaved from preproTRH upon delivery into the endoplasmic reticulum yielding proTRH. The conserved PGL sequence in the pYE26 peptide ensures the proper folding of proTRH within the lumen of the endoplasmic reticulum. The initial processing cleavage of proTRH by PC1/3 begins at the trans-Golgi network level generating an N-terminal and C-terminal intermediate forms. The intermediate forms of processed proTRH are then targeted to different secretory granules where processing continues by the action of the PCs, CPE/D and PAM until TRH and non TRH peptides are formed. The vertical bars on the right indicate in which intracellular compartment proTRH is cleaved and further procesed. Numbers indicates the positions of paired basic residues. Non TRH peptides are indicated in the proTRH molecule, and TRH is indicated by a black rectangle. Peptides are indicated as pXYZ nomenclature, where “p” means peptide, “X” is the first amino acid of each peptide, “Y” is the last one, and Z indicates the total number of amino acids in that given peptide. The nonTRH peptides are then targeted to different secretory granules ready for secretion. B depicts the proposed model of the unfolding process for proTRH after its initial cleavage by PC1/3, exposing potential sorting signals responsible for the targeting to different granules. Thus far a disulfide sequence has been identified in proTRH as an important sorting signal for the correct targeting of peptides to secretory granules. SS: signal sequence. ER: endoplasmic reticulum. TGN: trans Golgi network. ISGs: immature secretory granules. C-s-sC: disulfide bond. The reader should note that proTRH-derived peptides are named by “p” for peptide followed by the single letter amino acid designation for the first and last amino acid of the peptide, along with the peptide length in subscript. Where these peptides are first mentioned, they are followed by the longer prepro-TRH name that describes their amino acid residue positions within the precursor.
Fig.2
Fig.2
Subcellular distribution of proTRH intermediate and end products of processing, in transfected AtT20 cells encoding the TRH gene, and in primary cultures of hypothalamic neurons. The cells were fixed with 4% paraformaldehyde followed by immunostaining with different antibodies against the proTRH sequence. Fluorescein isothiocyanate conjugated to goat antirabbit globulin was used as a probe. Panel A, AtT20 cells: positive staining in the GC and TGN (arrows) using an antibody against proTRH and N-terminal intermediate forms (anti-pCC10). Bar =25μm. Panel C, AtT20 cells: cells immunostained with anti-TGN38 (arrows), a TGN marker. Bar = 50μm. Panel F, AtT20 cells: a typical positive staining along the plasma membrane (arrow heads), a common granule distribution of corticotropic cells, and processes (arrows) using anti-non-TRH peptides and anti-TRH. Bar = 25μm. Panel F, AtT20 cells; inset: typical positive staining of SGs by IEM using anti-pST10 antibodies (5 nm gold particles). Bar = 200μm. Panel H, AtT20 cells: positive staining in the GC and processes using an antibody that recognizes pro-TRH and C-terminal intermediate forms (anti-pYE17). Bar = 50μm. Panel B, Hypothalamic neurons: positive staining in the GC (arrow) and TGN using an antibody against proTRH and N-terminal intermediate forms, and in all boutons distributed along the neuronal processes (arrowheads) Bar = 50μm. Panel D, hypothalamic neurons: cells immunostained with anti-TGN38, a TGN marker. Bar = 50μm. Panel E, hypothalamic neurons, a higher magnification of panel B showing positive staining in stacked Golgi cisternae and in some forming granules (arrows) using the peroxidase-DAB reaction (arrows) Bar = 5μm. Panel G, hypothalamic neurons: positive fluorescence is observed only in neurites (arrowheads) and axon terminals, while the cell body remain unstained. Bar = 50μm. Panel G, hypothalamic neurons; inset: an IEM of neurites using peroxidase-DAB staining reaction. Of the two adjacent neurites shown, the lower one is positively stained (large arrows), whereas the upper one is negative (small arrow). Bar = 1μm. Panel I, hypothalamic neurons: positive staining in several areas of the cell body (arrowheads) and in all boutons distributed along the neuronal processes (arrowheads) using an antibody against pro-TRH and C-terminal intermediate forms. Bar = 25μm. Panel I, hypothalamic neurons, inset: a higher magnification of cytoplasmic areas from panel I showing positive staining in the endoplasmic reticulum and GC (arrows) as well as in SG near the plasma membrane (arrows). Bar = 2μm. nu, Nucleus; G, Golgi complex. The polyclonal antibodies used in this ICC are as follow: Anti-pCC10 [made against a synthetic decapeptide (Cys-Lys-Arg-Gln-His-Pro-Gly-Lys-Arg-Cys)], which recognizes prepro-TRH25–255 (26 kDa) prepro-TRH25–151 (15 kDa) prepro-TRH25–112 (9.5 kDa) prepro-TRH25–74 (6 kDa). Anti-pYE17 (made against prepro-TRH240–255), which recognizes prepro-TRH25–255 (26 kDa) prepro-TRH115–255 (16.5 kDa), prepro-TRH160–255 (10 kDa), prepro-TRH208–255 (5.4 kDa), anti-pST10 (made against preproTRH160–169), and anti-TRH. [Panels B, D, G, and I were reproduced with permission from E. A. Nillni et al.: Endocrinology 137:5651–5661, 1996 (36). Panels were reproduced with permission from E. A. Nillni and K. Sevarino: Endocr Rev. 1999 Oct;20(5):599-648. © The Endocrine Society.
Fig. 3
Fig. 3
N- and C-terminal end products of proTRH are partially located in different vesicles within the ME fibers. Sprague-Dawley rats were perfused with Karnovsky's fixative (A, inlet shows a panoramic micrograph of this region) or with 4% paraformaldehyde/0.15% glutaraldehyde in PBS (B-D). Panels C-D show an increased magnification of the panel B. Images show three classes of positive vesicles for either anti-pYE17 antibody alone (arrows-head), anti-pYE17 antibody alone (needles), or a combination of both antibodies (arrows). Panel 3E shows quantitative results obtained from sections labels first with anti-pYE17 (10 nm gold-particles), and then with anti-pYE27 (25nm gold-particles). Mean percentages represent the proportion of a particular positive vesicle compared to the total number of positivevesicles observed per micrograph. This Figure was reproduced with permission of Perello et al. J Biol Chem. 2008 Jul 18;283(29):19936-47.
Fig. 4
Fig. 4. Schematic representation of the TRH neuron with the most relevant inputs controlling its gene expression
The illustration shows the multiple signals affecting the TRH neuron coming from the peripheral circulation including leptin and T3, and from the ARC, α-MSH, NPY, and AgRP. The TRH promoter integrates each of these inputs to determine the set point of the HPT axis. The different hormonal inputs regulating the PCs are also represented.
Fig. 5
Fig. 5. Proposed model of leptin and NPY action on TRH neurons through the direct and indirect pathways
This diagram shows the two subgroups of TRH neurons recently identified based on their signaling modalities. Leptin acts directly on TRH neurons expressing ObRB through P-STAT3 signaling, and indirectly by acting on POMC neurons expressing ObRB that in turn release α-MSH and stimulate TRH neurons expressing the MC4 receptor through P-CREB signaling. A third unidentified group of TRH neurons is proposed to be potentially present in the PVN carrying both ObRb and MC4R. The TRH neurons carrying the MC4R are mainly involved in the regulation of the HPT axis, whereas the direct pathway could be essential in the obese condition. Other neurons stimulated by the melanocortin pathway might be involved in sympathetic activity or food intake regulation. NPY may regulate TRH neurons through mechanism 1 or 2 depending upon the status of the melanocortin system.
Fig. 6
Fig. 6. Integrated regulatory mechanisms controlling TRH transcription, posttranslational processing, and degradation by leptin and thyroid hormone
This illustration shows the multiple targets that leptin and T3 have in regulating the output of TRH. Tanycytes incorporate T4 and converted it to T3 by D2, and together with T3 coming from the periphery reach TRH neurons via specific transporters such as the monocarboxylate transporter (MCT8) inhibiting gene expression by affecting the TRH promoter through binding to the THRb2 isoform leading to the recruitment of cofactors such as SRC-1. PreproTRH, PC1/3, PC2, and PAM are inversely regulated by T3. Post-translational processing of proTRH occurs during the transport of the prohormone in the axons reaching the median eminence. The amount of TRH released from the axon terminals in the median eminence to the defenestrated capillaries can be controled by the degrading tanycyte-bound enzyme PPII, which is positively regulated by thyroid hormone. The potential effect of leptin via an activation of the sympathetic nervous system has been suggested, and in turn, increases the expression of BAT-UCP1 mRNA by the conversion of T4 to T3 facilitated by D2 increased activity. The staining in the PVN and ME was performed using an antibody against the proTRH sequence.
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References

    1. Nillni EA, Friedman TC, Todd RB, Birch NP, Loh YP, Jackson IM. Pro-thyrotropin-releasing hormone processing by recombinant PC1. J Neurochem. 1995;65:2462–72. - PubMed
    1. Nillni EA, Luo LG, Jackson IM, McMillan P. Identification of the thyrotropin-releasing hormone precursor, its processing products, and its coexpression with convertase 1 in primary cultures of hypothalamic neurons: anatomic distribution of PC1 and PC2. Endocrinology. 1996;137:5651–61. - PubMed
    1. Schaner P, Todd RB, Seidah NG, Nillni EA. Processing of prothyrotropin-releasing hormone by the family of prohormone convertases. J Biol Chem. 1997;272:19958–68. - PubMed
    1. Nillni EA, Xie W, Mulcahy L, Sanchez VC, Wetsel WC. Deficiencies in pro-thyrotropin-releasing hormone processing and abnormalities in thermoregulation in Cpefat/fat mice. J Biol Chem. 2002;277:48587–95. - PubMed
    1. Eipper BA, Stoffers DA, Mains RE. The biosynthesis of neuropeptides: peptide α-amidation. Annu Rev Neurosci. 1992;15:57–85. - PubMed

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