HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 277, Issue 50, 48587-48595, December 13, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/50/48587    most recent M206702200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nillni, E. A. Articles by Wetsel, W. C. Search for Related Content PubMed PubMed Citation Articles by Nillni, E. A. Articles by Wetsel, W. C. Social Bookmarking                      What's this?

Deficiencies in Pro-thyrotropin-releasing Hormone Processing and Abnormalities in Thermoregulation in Cpe^fat/fat Mice^*

Eduardo A. Nillni, Weihua Xie^§, Lawrence Mulcahy, Vanesa C. Sanchez, and William C. Wetsel^§¶

From the  Department of Medicine, Division of Endocrinology, Brown University, Rhode Island Hospital, Providence, Rhode Island 02903 and ^§ Departments of Psychiatry and Behavioral Sciences, Medicine (Endocrinology), and Cell Biology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina 27710

Cpe^fat/fat mice are obese, diabetic, and infertile. They have a mutation in carboxypeptidase E (CPE), an enzyme that converts prohormone intermediates to bioactive peptides. The Cpe^fat mutation leads to rapid degradation of the enzyme. To test whether pro-thyrotropin-releasing hormone (TRH) conversion to TRH involves CPE, processing was examined in the Cpe^fat/fat mouse. Hypothalamic TRH is depressed by at least 75% compared with wild-type controls. Concentrations of pro-TRH forms are increased in homozygotes. TRH-[Gly⁴-Lys⁵-Arg⁶] and TRH-[Gly⁴-Lys⁵] represent approximately 45% of the total TRH-like immunoreactivity in Cpe^fat/fat mice; they constitute ~1% in controls. Levels of TRH-[Gly⁴] were depressed in homozygotes. Because the hypothalamus contains some TRH, another carboxypeptidase must be responsible for processing. Immunocytochemical studies indicate that TRH neurons contain CPE- and carboxypeptidase D-like immunoreactivity. Recombinant CPE or carboxypeptidase D can convert synthetic TRH-[Gly⁴-Lys⁵] and TRH-[Gly⁴-Lys⁵-Arg⁶] to TRH-[Gly⁴]. When Cpe^fat/fat mice are exposed to cold, they cannot maintain their body temperatures, and this loss is associated with hypothalamic TRH depletion and reduction in thyroid hormone. These findings demonstrate that the Cpe^fat mutation can affect not only carboxypeptidase activity but also endoproteolysis. Because Cpe^fat/fat mice cannot sustain a cold challenge, and because alterations in the hypothalamic-pituitary-thyroid axis can affect metabolism, deficits in pro-TRH processing may contribute to the obese and diabetic phenotype in these mice.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				K. R. Vella and A. N. Hollenberg The Ups and Downs of Thyrotropin-Releasing Hormone Endocrinology, May 1, 2009; 150(5): 2021 - 2023. [Full Text] [PDF]

				D. Bousquet-Moore, X. M. Ma, E. A. Nillni, T. A. Czyzyk, J. E. Pintar, B. A. Eipper, and R. E. Mains Reversal of Physiological Deficits Caused by Diminished Levels of Peptidylglycine {alpha}-Amidating Monooxygenase by Dietary Copper Endocrinology, April 1, 2009; 150(4): 1739 - 1747. [Abstract] [Full Text] [PDF]

				A. Romero, I. Cakir, C. A. Vaslet, R. C. Stuart, O. Lansari, H. A. Lucero, and E. A. Nillni Role of a Pro-sequence in the Secretory Pathway of Prothyrotropin-releasing Hormone J. Biol. Chem., November 14, 2008; 283(46): 31438 - 31448. [Abstract] [Full Text] [PDF]

				M. Perello, R. C. Stuart, C. A. Vaslet, and E. A. Nillni Cold Exposure Increases the Biosynthesis and Proteolytic Processing of Prothyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus via {beta}-Adrenoreceptors Endocrinology, October 1, 2007; 148(10): 4952 - 4964. [Abstract] [Full Text] [PDF]

				L. D. Fricker Neuropeptidomics to Study Peptide Processing in Animal Models of Obesity Endocrinology, September 1, 2007; 148(9): 4185 - 4190. [Abstract] [Full Text] [PDF]

				E. A. Nillni Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin Endocrinology, September 1, 2007; 148(9): 4191 - 4200. [Abstract] [Full Text] [PDF]

				V. P. Espinosa, M. Ferrini, X. Shen, K. Lutfy, E. A. Nillni, and T. C. Friedman Cellular colocalization and coregulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E175 - E186. [Abstract] [Full Text] [PDF]

				B Beck Neuropeptide Y in normal eating and in genetic and dietary-induced obesity Phil Trans R Soc B, July 29, 2006; 361(1471): 1159 - 1185. [Abstract] [Full Text] [PDF]

				M. Perello, T. Friedman, V. Paez-Espinosa, X. Shen, R. C. Stuart, and E. A. Nillni Thyroid Hormones Selectively Regulate the Posttranslational Processing of Prothyrotropin-Releasing Hormone in the Paraventricular Nucleus of the Hypothalamus Endocrinology, June 1, 2006; 147(6): 2705 - 2716. [Abstract] [Full Text] [PDF]

				M. Hosaka, T. Watanabe, Y. Sakai, T. Kato, and T. Takeuchi Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules J. Cell Sci., October 15, 2005; 118(20): 4785 - 4795. [Abstract] [Full Text] [PDF]

				L. Marzban, G. Soukhatcheva, and C. B. Verchere Role of Carboxypeptidase E in Processing of Pro-Islet Amyloid Polypeptide in {beta}-Cells Endocrinology, April 1, 2005; 146(4): 1808 - 1817. [Abstract] [Full Text] [PDF]

				P.-S. Tsai, S. M. Moenter, H. R. Postigo, M. El Majdoubi, T. R. Pak, J. C. Gill, S. Paruthiyil, S. Werner, and R. I. Weiner Targeted Expression of a Dominant-Negative Fibroblast Growth Factor (FGF) Receptor in Gonadotropin-Releasing Hormone (GnRH) Neurons Reduces FGF Responsiveness and the Size of GnRH Neuronal Population Mol. Endocrinol., January 1, 2005; 19(1): 225 - 236. [Abstract] [Full Text] [PDF]

				S. Srinivasan, D. O. Bunch, Y. Feng, R. M. Rodriguiz, M. Li, R. L. Ravenell, G. X. Luo, A. Arimura, L. D. Fricker, E. M. Eddy, et al. Deficits in Reproduction and Pro-Gonadotropin-Releasing Hormone Processing in Male Cpefat Mice Endocrinology, April 1, 2004; 145(4): 2023 - 2034. [Abstract] [Full Text] [PDF]