A novel regulator of thirst behavior: phoenixin

Abstract

There are examples of physiological conditions under which thirst is inappropriately exaggerated, and the mechanisms for these paradoxical ingestive behaviors remain unknown. We are interested in thirst mechanisms across the female life cycle and have identified a novel mechanism through which ingestive behavior may be activated. We discovered a previously unrecognized endogenous hypothalamic peptide, phoenixin (PNX), identified physiologically relevant actions of the peptide in brain and pituitary gland to control reproductive hormone secretion in female rodents, and in the process identified the previously orphaned G protein-coupled receptor Gpr173 to be a potential receptor for the peptide. Labeled PNX binding distribution in brain parallels areas known to be important in ingestive behaviors as well in areas where gonadal steroids feedback to control estrous cyclicity (Stein LM, Tullock CW, Mathews SK, Garcia-Galiano D, Elias CF, Samson WK, Yosten GLC, Am J Physiol Regul Integr Comp Physiol 311: R489–R496, 2016). We have demonstrated upregulation of Gpr173 during puberty, fluctuations across the estrous cycle, and, importantly, upregulation during the last third of gestation. It is during this hypervolemic, hyponatremic state that both vasopressin secretion and thirst are inappropriately elevated in humans. Here, we show that central administration of PNX stimulated water drinking in both males and females under ad libitum conditions, increased water drinking after overnight fluid deprivation, and increased both water and 1.5% NaCl ingestion under fed and hydrated conditions. Importantly, losartan pretreatment blocked the effect of PNX on water drinking, and knockdown of Gpr173 by use of short interfering RNA constructs significantly attenuated water drinking in response to overnight fluid deprivation. These actions, together with the stimulatory action of PNX on vasopressin secretion, suggest that this recently discovered neuropeptide may impact the recruitment of critically important neural circuits through which ingestive behaviors and endocrine mechanisms that maintain fluid and electrolyte homeostasis are regulated.

Modulatory effect of olanzapine on SMIM20/phoenixin, NPQ/spexin and NUCB2/nesfatin-1 gene expressions in the rat brainstem

“…PNX also influences the excitability of solitary nucleus neurons, and its action depends on environmental stress factors and glucocorticoids [ 17 ]. PNX stimulates the secretion of vasopressin and is an element of neuronal loops that regulate the endocrine and behavioral mechanisms of electrolyte homeostasis in the body [ 18 ]. Recently, studies have also suggested a neuroprotective effect of PNX-20 dependent on SIRT1 and the participation of this neuropeptide in the modulation of inflammatory reactions in the CNS [ 19 ].…”

Non-Reproductive Effects of Estradiol: Hydromineral Homeostasis Control

“…In this context, our group demonstrated upregulation of GPR173 during late post-puberty in the PVN, and importantly, upregulation during the last third of pregnancy in the hypothalamus. Moreover, it was observed an increase in the hypothalamic levels of PNX and AVP across pregnancy compared with levels present during diestrus with a positive correlation between both peptides [84]. Thus, these results suggest an important role of PNX on AVP release during late pregnancy, which can help to provide potential pharmacological targets for preventing the development of cardiovascular diseases across pregnancy.…”

“…Despite there are no differences between males and females on PNX-induced AVP release, a potential estrogen response element (ERE) upstream of PNX was identified, suggesting that ovarian hormones, especially E2, can modulate PNX [80,83]. Consistent with this idea, ovarian failure induced by OVX induces downregulation of PNX compared with intact females in the hypothalamus [84].…”

Pre-metazoan origin of neuropeptide signalling

“…Recently, neuropeptidomic searches in arthropod transcriptomes revealed phoenixin precursors with conserved cleavage sites to produce the mature PNX peptide PNX14 and PNX-20 (Nguyen et al 2018). PNX is involved in many different physiological functions in mammals, such as cardio-modulation, memory, anxiety, food intake and reproduction (Clarke and Dhillo 2019;Schalla and Stengel 2019;Billert et al 2020;Haddock et al 2020;Ma et al 2020;Schalla et al 2020;Friedrich and Stengel 2021;Yao et al 2021). The mechanism of signalling of PNX, an orphan ligand, remains unclear.…”