Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin

Abstract

Recent evidence demonstrated that posttranslational processing of neuropeptides is critical in the pathogenesis of obesity. Leptin or other physiological changes affects the biosynthesis and processing of many peptides hormones as well as the regulation of the family of prohormone convertases responsible for the maturation of these hormones. Regulation of energy balance by leptin involves regulation of several proneuropeptides such as proTRH and proopiomelanocortin. These proneuropeptide precursors require for their maturation proteolytic cleavage by the prohormone convertases 1 and 2 (PC1/3 and PC2). Because biosynthesis of mature peptides in response to leptin requires prohormone processing, it is hypothesized that leptin might regulate hypothalamic PC1/3 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Leptin has been shown to increase PC1/3 and PC2 promoter activities, and starvation of rats, leading to low serum leptin levels, resulted in a decrease in PC1/3 and PC2 gene and protein expression in the paraventricular and arcuate nucleus of the hypothalamus. Changes in nutritional status also changes proopiomelanocortin processing in the nucleus of the solitary tract, but this is not reversed by leptin. The PCs are also physiologically regulated by states of hyperthyroidism, hyperglycemia, inflammation, and suckling, and a recently discovered nescient helix-loop-helix-2 transcription factor is the first one to show an ability to regulate the transcription of PC1/3 and PC2. Therefore, the coupled regulation of proneuropeptide/processing enzymes may be a common process, by which cells generate more effective processing of prohormones into mature peptides. (Endocrinology 148: 4191-4200, 2007)

Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH

“…When we infused NPY directly into the PVN, PC2 levels in PVN tissue decreased similarly to what we observed in ARC tissue with icv NPY infusions. This decrease in PVN PC2 could lead to less TRH, as PC2 plays a role in pro-TRH processing (44). Moreover, we supported previous findings by Sarkar and Lechan (59) that NPY decreases the activation of CREB by ␣-MSH in TRH neurons.…”

“…Thus, NPY downregulation of cAMP may decrease Egr-1. In addition, PC2 contains two Egr-1 binding sites in its promoter (27,44), and the human PC2 promoter is activated by Egr-1 (27). This pathway is illustrated in Fig.…”

“…However, it remains unknown whether NPY regulates the production of ␣-MSH. To generate ␣-MSH, its prohormone POMC must undergo a series of proteolytic cleavages catalyzed by the enzymes prohormone convertase-1 [PC1, also referred to as PC3 (63)] and prohormone convertase-2 (PC2), followed by further modification via carboxypeptidase E (CPE) and N-acetyltransferase (11,44,67). Because of this maturation process, it is critical to know whether NPY regulates ␣-MSH peptide content rather than to focus only on changes at the level of POMC transcription.…”

“…This is especially important when studying peptide hormones, as most peptide hormones are initially synthesized as large inactive precursors that are posttranslationally processed into smaller bioactive products, stored in secretory vesicles, and released when the cell receives specific stimuli (61). Prohormone processing is an important but understudied mechanism that is essential not only in rodents, but also in humans (44,45,65,67). For example, several landmark studies demonstrate that the abnormal processing of prohormones such as POMC causes obesity in humans.…”

Acute starvation alters lipopolysaccharide-induced fever in leptin-dependent and -independent mechanisms in rats

“…Although the present correlational evidence implicates POMC in the leptin-mediated maintenance of the fever response, functional studies are needed to test whether and how this peptide influences the late phase of fever. POMC peptide is a precursor for several biologically active neuropeptides including ␣-MSH, ␤-endorphin, and ACTH (40). Of particular interest to the current study is ␤-endorphin as blockade of -opioid receptor, one of the receptors for ␤-endorphin either by specific antagonists or genetic mutation abrogates the fever response induced by classical pyrogens including LPS (4,5,16,44,61) via several different mechanisms, including a central hypothermic action, peripheral vasodilation, and peripheral antipyretic activity (44).…”