A systematic scoping review of the multifaceted role of phoenixin in metabolism: insights from in vitro and in vivo studies

Abstract

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.

Keywords: glycolysis; metabolism; mitochondria; mitochondrial respiration; phoenixin (PNX).

Figure 1

Illustration of the signaling pathways regulated by PNX. PNX has been shown to activate the cAMP/PKA and cAMP/Epac signaling pathways while inhibiting the PERK/eIF2α signaling pathway. This regulation of signaling pathways is crucial for modulating various biological processes, including reproductive systems, glucose and lipid metabolism, and apoptosis. ATP, Adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CREB, cAMP-response element binding protein; GnRH, Gonadotropin hormone-releasing hormone; C/EBPs, CAAT-enhancer-binding proteins; Oct-01, Organic cation transporter 1; PPARγ, Peroxisome Proliferator-Activated Receptor Gamma; Fabp-4, Fatty Acid-Binding Proteins 4; ATF, Activating Transcription Factor; CHOP, C/EBP-homologous protein; eIF2α, Eukaryotic translation initiation factor 2α.

Figure 2

Flowchart outlining the search strategy employed in researching the correlation between PNX and metabolism (37).

Figure 3

Distribution of reviewed studies by experimental type and subject sex: (A) Classification of reviewed studies based on the type of study, (B) Distribution of reviewed in vivo studies based on sex, (C) Distribution of in vitro study based on sex. This figure illustrates the breakdown of analyzed in vitro and in vivo studies, further categorized by the sex of subjects used (male, female, or unspecified). The visualization allows for a quick assessment of sex representation across different experimental approaches, highlighting trends in the inclusion of male, female, or sex-unspecified subjects and revealing any gaps in sex-specific research within the reviewed studies.

Figure 4

The expression of PNX in the hypothalamus. PVN, paraventricular nucleus; SON, supraoptic nucleus; ARC, arcuate nucleus; DMH, dorsomedial hypothalamic nucleus; VMH, ventromedial hypothalamus; SCN, suprachiasmatic nucleus; MB, mammillary bodies; PH, posterior hypothalamus.