Qin Xiangfeng, Ye Cheng, Chan Ying Wai, Wong Anderson O L
School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Front Endocrinol (Lausanne). 2025 Apr 29;16:1570716. doi: 10.3389/fendo.2025.1570716. eCollection 2025.
Phoenixin (PNX) is a novel peptide with diverse functions mediated by the orphan receptor GPR173. It also plays a role in appetite control, but the effect is not consistent across species and the mechanisms involved are still unclear. Using goldfish as a model, the mechanisms underlying feeding regulation by PNX were examined. In our study, two isoforms of PNX, PNXa and PNXb, and one form of GPR173 were cloned in goldfish and found to be highly conserved compared to their counterparts in other species based on sequence alignment, phylogenetic analysis, and protein modeling. Using RT-PCR, PNXa/b and GPR173 were confirmed to be ubiquitously expressed at the tissue level. In goldfish, transcript expression of PNXa/b and GPR173 in the liver and brain areas including the telencephalon, hypothalamus, and optic tectum, were elevated by food intake but suppressed by fasting. Intraperitoneal (IP) and intracerebroventricular (ICV) injections of PNX20a and PNX20b, the mature peptides for PNXa and PNXb respectively, were both effective in increasing foraging behavior, surface motility, and food intake. Furthermore, the expression of orexigenic factors (neuropeptide Y (NPY), agouti-related peptide, orexin, and apelin) was elevated with parallel drops in anorexigenic signals (cholecystokinin, pro-opiomelanocortin, corticotropin-releasing hormone, and melanin-concentrating hormone) in the telencephalon, hypothalamus, and/or optic tectum. In the same brain areas, receptor expression for anorexigenic factors (leptin and adiponectin) was attenuated with concurrent rises in receptor levels for orexigenic signals (NPY and ghrelin). In our study, after IP injection of PNX20a/b, downregulation of leptin, adiponectin, and other feeding inhibitors expressed in the liver was also noted. Our findings reveal that PNX20a/b can serve as an orexigenic factor in goldfish. PNX signals (both central and peripheral) can be induced by food intake and act within the brain to trigger foraging and food consumption via differential modulation of appetite-regulating factors and their receptors in different brain areas. The feeding responses observed may also involve a hepatic component with PNX repression of feeding inhibitors expressed in the liver. The PNX signals induced by feeding may form a feedforward loop to maintain/prolong food intake during a meal prior to the onset of satiation response in our fish model.
胃动素（PNX）是一种由孤儿受体GPR173介导发挥多种功能的新型肽。它在食欲控制中也起作用，但在不同物种间的作用效果并不一致，其涉及的机制仍不清楚。本研究以金鱼为模型，探究了PNX调节摄食的潜在机制。在本研究中，克隆了金鱼的两种PNX亚型，即PNXa和PNXb，以及一种GPR173形式，通过序列比对、系统发育分析和蛋白质建模发现，与其他物种的对应物相比，它们具有高度保守性。采用逆转录聚合酶链反应（RT-PCR）技术证实，PNXa/b和GPR173在组织水平上广泛表达。在金鱼中，摄食可使肝脏以及包括端脑、下丘脑和视顶盖在内的脑区中PNXa/b和GPR173的转录本表达升高，而禁食则使其受到抑制。分别腹腔注射（IP）和脑室内注射（ICV）PNXa和PNXb的成熟肽PNX20a和PNX20b，均可有效增加觅食行为、表面活动能力和食物摄入量。此外，在端脑、下丘脑和/或视顶盖中，食欲促进因子（神经肽Y（NPY）、刺鼠相关肽、食欲素和脂联素）的表达升高，同时食欲抑制信号（胆囊收缩素、阿黑皮素原、促肾上腺皮质激素释放激素和促黑素细胞激素）平行下降。在相同脑区，食欲抑制因子（瘦素和脂联素）的受体表达减弱，同时食欲促进信号（NPY和胃饥饿素）的受体水平升高。在本研究中，腹腔注射PNX20a/b后，还发现肝脏中表达的瘦素、脂联素和其他摄食抑制因子下调。我们的研究结果表明，PNX20a/b可作为金鱼的一种食欲促进因子。PNX信号（中枢和外周）可由摄食诱导，并在脑内发挥作用，通过对不同脑区食欲调节因子及其受体的差异调节来触发觅食和食物消耗。观察到的摄食反应可能还涉及肝脏成分，即PNX抑制肝脏中表达的摄食抑制因子。在我们的鱼类模型中，摄食诱导的PNX信号可能形成一个前馈回路，以在饱腹感反应开始之前的进食过程中维持/延长食物摄入量。
