Phoenixin (PNX) is an emerging neuropeptide that plays a significant role in regulating metabolism and reproduction. This comprehensive review examines findings from human, in vivo, and in vitro studies to elucidate the functions of PNX in metabolic processes. PNX has been identified as a key player in essential metabolic pathways, including energy homeostasis, glucose, lipid and electrolyte metabolism, and mitochondrial dynamics. It modulates food and fluid intake, influences glucose and lipid profiles, and affects mitochondrial biogenesis and function. PNX is abundantly expressed in the hypothalamus, where it plays a crucial role in regulating reproductive hormone secretion and maintaining energy balance. Furthermore, PNX is also expressed in peripheral tissues such as the heart, spleen, and pancreas, indicating its involvement in the regulation of metabolism across central and peripheral systems. PNX is a therapeutic peptide that operates through the G protein-coupled receptor 173 (GPR173) at the molecular level. It activates signaling pathways such as cAMP-protein kinase A (PKA) and Epac-ERK, which are crucial for metabolic regulation. Research suggests that PNX may be effective in managing metabolic disorders like obesity and type 2 diabetes, as well as reproductive health issues like infertility. Since metabolic processes are closely linked to reproduction, further understanding of PNX’s role in these areas is necessary to develop effective management/treatments. This review aims to highlight PNX’s involvement in metabolism and identify gaps in current knowledge regarding its impact on human health. Understanding the mechanisms of PNX’s action is crucial for the development of novel therapeutic strategies for the treatment of metabolic disorders and reproductive health issues, which are significant public health concerns globally.
Phoenixin (PNX) is a neuropeptide that has garnered significant interest in the scientific community over the past eight years. It has been identified across various species, including humans, rodents, pigs, cows, chickens, Xenopus, and zebrafish, highlighting its evolutionary conservation and potential biological significance.
PNX peptide derived from the C-terminal of the small integral membrane protein 20 (SMIM20) and primarily exists in two amidated isoforms: a 14-amino-acid peptide (PNX-14) and a longer, N-terminal-extended 20-amino-acid peptide. PNX is widely distributed across various tissues, including the hypothalamus, heart, spleen, thymus, skin, ovaries, testes, adipose tissue, and pancreas. Notably, PNX-20 is predominantly expressed in the hypothalamus, while PNX-14 is more abundant in the heart and spinal cord. Despite these sequence length variations, they appear to function similarly.
PNX was characterized as a reproductive peptide or hormone upon its discovery. However, the specific expression levels of PNX in the brain and other tissues with respect to sex differences remain undetermined. In contrast, the well-known reproductive hormones have clearly defined expression patterns. Previous reviews have noted that reproductive hormone expression varies according to sex. Reproductive hormones such as gonadotrophin-releasing hormones (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, estrogen, and testosterone are present in both sexes. However, the expression levels and patterns of these reproductive hormones differ between sexes. In terms of localization, GnRH, LH and FSH were not sexually dimorphic. However, estrogen and testosterone were localized differently in males and females.
Previous studies have shown that the distribution of PNX in the brain is similar in both sexes. PNX is expressed in the arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV), both of which contain androgen receptors (AR) in males and females. Additionally, estrogen receptors (ER) are present in hypothalamic regions that express PNX, including the paraventricular nucleus (PVN), ARC, and AVPV. Furthermore, recent reviews have noted that the promoter region of PNX contains binding sites for ER. The presence of both AR and ER in PNX-expressing nuclei, along with ER binding sites in the promoter region, suggests that sex may influence the functional role of PNX. Further investigation into the sex-specific expression of PNX is needed to better understand its role and the associated sex-based differences.
PNX exerts its effects primarily through the G protein-coupled receptor 173 (GPR173). The binding of PNX to GPR173 is postulated to activate various intracellular signaling pathways, including the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), cAMP/exchange proteins directly activated by cAMP (Epac), phosphatase and tensin homolog (PTEN)/protein kinase B (Akt) and phosphoinositide 3-Kinase (PI3K)/Akt Pathway. Regulation of these pathways leads to downstream effects on gene and protein expression, biological processes, and physiological responses. Nonetheless, whether PNX-14 and PNX-20 differ in their bioactivity or bind to distinct receptors or receptor subtypes remains uncertain.
Early findings on PNX have demonstrated its crucial roles in reproduction, particularly in regulating reproductive hormone secretion. PNX is found to induce the stimulation of LH secretion by potentiating the activity of GnRH. At the gonadal level, PNX affects follicular development and modulates the expression of gonadotropins across various species, including fish and mammals. Nonetheless, recent studies have indicated that PNX is involved in a wide range of biological and physiological processes that cover anxiety, memory, oxidative stress, inflammation, cell proliferation and differentiation. Interestingly, recent studies have highlighted the role of PNX in regulating the biological process of metabolism, particularly its influences on the regulation of food and fluid intake, glucose, lipid, and electrolyte metabolism, as well as mitochondrial dynamics and energy homeostasis.
It is well established that reproduction is closely interconnected to metabolic function, as metabolic health significantly influences reproductive processes. Various metabolic hormones, such as insulin and leptin, impact the levels of reproductive hormones and, consequently, reproductive function. Recent findings on PNX further strengthen the link between these two physiological functions. Despite significant progress in understanding the role of PNX, many questions about its involvement in metabolism remain elusive. Discussing the current findings on metabolic regulation by PNX is pivotal, as it holds the potential to unveil groundbreaking insights into its profound influence on energy regulation, metabolic homeostasis, and subsequent health outcomes.
Therefore, this scoping review aimed to comprehensively map the current understanding of the role of PNX in metabolism. By identifying knowledge gaps and research trends, this review paves the way for future studies to develop targeted therapeutic strategies that modulate the impact of PNX on metabolism, potentially offering novel treatment options and improving human health. These strategies could address the neuroendocrine dysregulation associated with metabolic diseases, highlighting the broader implications of PNX in maintaining metabolic homeostasis and its potential as a prognostic marker in clinical settings.
This review followed the five stages outlined in the Arksey and O’Malley framework.
The following questions guided this scoping review of understanding the role of PNX in metabolism: What are the specific mechanisms underlying the involvement of PNX in energy homeostasis and metabolic regulation? What are the downstream signaling pathways activated by PNX that modulate metabolism regulation? How does PNX affect mitochondrial respiration rates and adenosine triphosphate (ATP) production in various metabolic contexts? What is the impact of PNX on glucose metabolism, insulin sensitivity, and pancreatic beta-cell function in health and metabolic disorders? How is PNX dysregulation implicated in the pathogenesis of metabolic disorders such as obesity, insulin resistance, dyslipidemia, and metabolic syndrome?
A systematic and comprehensive search strategy was employed to identify relevant studies. Four electronic databases (PubMed, Scopus, Google Scholar and Web of Science) were used to search for the articles published between 2013 and 2024. The data search was conducted on 30 th May 2024 using relevant keywords identified from Medical Subject Headings (MeSH). Keywords used for the data collection were PNX, metabolism, mitochondria, glycolysis and mitochondria respiration.
Two independent authors screened citation titles and abstracts and then reviewed potentially relevant articles in full, with a third author responsible for resolving any arising conflicts. The screening process was carried out using Covidence. The systematic scoping review employed a stringent selection process to ensure the reliability and comprehensiveness of the included studies. Initially, articles were screened against predefined inclusion criteria, tailored to the revie
