Deficiencies in Pro-thyrotropin-releasing Hormone Processing and Abnormalities in Thermoregulation in CpeMice

Nillni, Eduardo A.; Xie, Weihua; Mulcahy, Lawrence; Sanchez, Vanesa C.; Wetsel, William C.

doi:10.1074/jbc.m206702200

Cited by 56 publications

(55 citation statements)

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“…As an adaptive response to increase body temperature, cold exposure is also associated with increased expression of preproTRH in hypophysiotropic neurons and, in turn, increased secretion of TSH and a subsequent increase in thyroid hormone levels (72). In studies with the Cpe fat mouse, we demonstrated that the Cpe fat mutation might affect TRH biosynthesis and that it caused aberrant proTRH processing (38); this suggests that various products derived from proTRH can be independently regulated under altered physiological conditions. Interestingly, genetically obese (ob/ob) mice exposed to a cold environment showed a low increase in brown adipose tissue thermogenesis, a delayed increase in thyroxine 5′-deiodinase, and a reduced increase in serum T 3 level, and these mice became hypothermic (73,74).…”

Section: Figurementioning

confidence: 78%

“…The role of CPE has been elucidated in Cpe fat /Cpe fat mice, which lack functional CPE because of a naturally occurring mutation (37). We found that hypothalamic TRH in these mice was depressed by at least 75% compared with that in wild-type controls (38). These mice cannot maintain their body temperatures when exposed to cold due to substantial decrease of hypothalamic TRH and reduction in thyroid hormone.…”

Section: Introductionmentioning

confidence: 84%

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Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

Sanchez¹,

Goldstein²,

Stuart³

et al. 2004

J. Clin. Invest.

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Regulation of energy balance by leptin involves regulation of several neuropeptides, including thyrotropinreleasing hormone (TRH).Synthesized from a larger inactive precursor, its maturation requires proteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2). Since this maturation in response to leptin requires prohormone processing, we hypothesized that leptin might regulate hypothalamic PC1 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Using hypothalamic neurons, we found that leptin stimulated PC1 and PC2 mRNA and protein expression and also increased PC1 and PC2 promoter activities in transfected 293T cells. Starvation of rats, leading to low serum leptin levels, decreased PC1 and PC2 gene and protein expression in the paraventricular nucleus (PVN) of the hypothalamus. Exogenous administration of leptin to fasted animals restored PC1 levels in the median eminence (ME) and the PVN to approximately the level found in fed control animals. Consistent with this regulation of PCs in the PVN, concentrations of TRH in the PVN and ME were substantially reduced in the fasted animals relative to the fed animals, and leptin reversed this decrease. Further analysis showed that proteolytic cleavage of pro-thyrotropin-releasing hormone (proTRH) at known PC cleavage sites was reduced by fasting and increased in animals given leptin. Combined, these findings suggest that leptin-dependent stimulation of hypothalamic TRH expression involves both activation of trh transcription and stimulation of PC1 and PC2 expression, which lead to enhanced processing of proTRH into mature TRH.

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Section: Figurementioning

confidence: 78%

Section: Introductionmentioning

confidence: 84%

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

Sanchez¹,

Goldstein²,

Stuart³

et al. 2004

J. Clin. Invest.

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“…shown by the presence of unprocessed prohormone intermediates such as prodynorphin intermediates and ␣-melanocyte-stimulating hormone (␣MSH) precursors (Berman et al, 2001), pro-thyrotropin-releasing hormone intermediates (Nillni et al, 2002), procholecystokinin intermediates (Lacourse et al, 1998), and proinsulin and cocain-and amphetamine-related transcript (CART) precursors (Cawley et al, 2004) in Cpe fat mice and CPE-knockout mice. Among these hormones, inefficient production of mature ␣MSH and CART is suggested to enhance food intake and lead to adult-onset obesity in the Cpe fat mouse and CPE-knockout mouse (Zimmermann-Belsing andFeldt-Rasmussen, 2004: Cawley et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules

Hosaka

Watanabe

Sakai

et al. 2005

Journal of Cell Science

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Secretogranin III (SgIII) and carboxypeptidase E (CPE) bind specifically to cholesterol-rich secretory granule (SG) membranes. We previously showed that SgIII binds chromogranin A (CgA) and targets CgA to the SGs in endocrine cells. We investigated the binding of SgIII and CPE because they frequently localize close to the periphery of SGs, and they bind each other in mouse corticotrope-derived AtT-20 cells. In Cpefat mouse corticotropes, which have defective CPE, proopiomelanocortin (POMC)-derived adrenocorticotrophin hormone (ACTH)-containing peptides were distributed over the entire surface of the SGs, and displayed a regulated secretion by secretagogues. The Cpefat pituitary exhibited elevated levels of SgIII and CgA, which suggests that they compensate for a sorting function of CPE for POMC and its intermediates to ACTH. Indeed, both SgIII and CgA were able to bind POMC-derived intermediates. In a competitive pull-down assay, excessive SgIII led to a decrease in CPE-bound POMC-derived intermediate molecules, and SgIII pulled-down by anti-ACTH antibody increased proportionately. We suggest that SgIII and CPE form the separate functional sorting complex by anchoring to cholesterol-rich SG membranes, and POMC-derived peptides are transferred from CPE to SgIII, and subsequently to CgA.

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“…1). Extensive research has been done during the last two decades to understand the post-translational processing of proTRH (11)(12)(13), the convertases responsible for pro-TRH cleavage (14 -17) the intracellular sites of proTRH processing (18,19). More recently the importance of the initial cleavage for proTRH sorting (20), and the implications of the C-terminal disulfide bond in this process (21) has been uncovered.…”

mentioning

confidence: 99%

Role of a Pro-sequence in the Secretory Pathway of Prothyrotropin-releasing Hormone

Romero

Çakır

Vaslet

et al. 2008

Journal of Biological Chemistry

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The biogenesis of rat thyrotropin releasing hormone (TRH) involves the processing of its precursor (proTRH) into five biologically active TRH peptides and several non-TRH peptides where two of them had been attributed potential biological functions. This process implicates 1) proper folding of proTRH in the endoplasmic reticulum after its biosynthesis and exit to the Golgi apparatus and beyond, 2) initial processing of proTRH in the trans Golgi network and, 3) sorting of proTRH-derived peptides to the regulated secretory pathway. Previous studies have focused on elucidating the processing and sorting determinants of proTRH. However, the role of protein folding in the sorting of proTRH remains unexplored. Here we have investigated the role in the secretion of proTRH of a sequence comprising 22 amino acid residues, located at the N-terminal region of proTRH, residues 31-52. Complete deletion of these 22 amino acids dramatically compromised the biosynthesis of proTRH, manifested as a severe reduction in the steady state level of pro-TRH in the endoplasmic reticulum. This effect was largely reproduced by the deletion of only three amino acid residues, 40 PGL 42 , within the proTRH 31-52 sequence. The decreased steady state level of the mutant ⌬PGL was due to enhanced endoplasmic reticulum-associated protein degradation. However, the remnant of ⌬PGL that escaped degradation was properly processed and sorted to secretory granules. Thus, these results suggest that the N-terminal domain within the prohormone sequence does not act as "sorting signal" in late secretion; instead, it seems to play a key role determining the proper folding pathway of the precursor and, thus, its stability.

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Deficiencies in Pro-thyrotropin-releasing Hormone Processing and Abnormalities in Thermoregulation in CpeMice

Abstract: Cpefat/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.

Cited by 56 publications

References 56 publications

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone

Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules

Role of a Pro-sequence in the Secretory Pathway of Prothyrotropin-releasing Hormone

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