All About Phoenixin: Pros And Cons Of Phoenixin And GPR173

Phoenixin is a peptide that regulates reproductive function, behavior, sensory perception, memory retention, cardiovascular health and food intake. R

Phoenixin was originally discovered in 2013 when algorithmic screening for unknown peptides and was found to be in humans, rodents, pigs, cows, chicken, xenopus, silurana, zebrafish and fugu, with only slight variabilities in amino acid sequencing. R

Phoeneixin acts via multiple pathways such as the Brain-Gut axis, the skin-brain axis, hypothalamus pituitary genital (HPG) axis etc. R R R

Phoenixin And Multiple Body-Axes

In the brain, phoenixin is found in the (has downstream effects on gastrointestinal tract): R R

• paraventricular nucleus (PVN)
• arcuate nucleus (ARC)
• ventromedial hypothalamus (VMH)
• magnocellular and parvocellular supraoptic nucleus (SON)
• dorsal hypothalamus
• zona incerta
• lateral hypothalamus
• perifornical area
• substantia nigra
• Edinger-Westphal nucleus
• dorsal motor nucleus of the vagus nerve
• supraoptic retrochiasmatic nucleus
•  nucleus of the solitary tract (NTS)

In the spinal cord and sensory glia, phoenixin is found in: R

• the superficial dorsal horn of cervical, thoracic, lumbar and sacral segments (especially in laminae I and II, but also in deeper laminae)
• dorsal root, nodose, and trigeminal ganglion

In other organ systems, phoenixin is found in: R R R

• Heart
• Thymus
• Esophagus
• Stomach
• Spleen
• Pancreas
• Lung
• Kidney
• Jujunum
• Duodenum
• Ilieum
• Colon
• Epidermis
• Dermis

Phoenixin (mainly exists in 2 active forms: -14 and -20) binds to the receptor GPR173 (SREB3) for a multitude of functions in the body. R R R R

For example, blocking GPR173's binding ability stops phoenixin's action on reproductive function. R R R

I believe reduced phoenixin may produce some of the effects as seen of eating a keto diet: weight loss and decreased wanting to eat/have sex, but increased cognition. 

When you eat a high fat diet, you reduce phoenixin, which may thus decrease (day light) feeding and reproduction-inducing hormones.

When phoenixin levels are high you may get increased will to eat, reproduce, and may gain weight.

In terms of memory, higher levels of phoenixin may be better for memory recall, but worse for logical memory

So finding the right balance and circadian rhythm of phoenixin and GPR173 expression is the key to making this peptide harmonious in your body.

1. Reduces Anxiety

Phoenixin can quench anxiety. R R R R

Higher levels of phoenixin has shown to reduce anxiety and increase exploratory behavior in animal models. R R R

In humans with Generalized Anxiety Disorder (GAD), higher plasma levels of phoenixin were correlated with lower anxiety. R

2. Plays A Role In Reproduction, Fluid Retention, and Puberty

Phoenixin's can change sexual reproduction desire (effects on reproductive health are regulated via GPR173). R R R

It increases sexual reproductive function by stimulation of hormone production. R

For example, activation of GPR173 via phoenixin can increase plasma vasopressin (AVP) levels, induce expression of Luteinizing Hormone (LH) via potentiation of gonadotropin-releasing hormone (GnRH) and induce secretion of kisspeptin. R R R

By acting on AVP, phoenixin can increase fluid retention. R

Given that GnRH can stimulate puberty, phoenixin may be involved in its mechanism. R

3. Stimulates Food Intake

Phoenixin acts as an orexigenic peptide and can stimulate feeding (food specific and not water intake), but only has effects during the day (not at night). R R R

This may indicate that phoenixin has a circadian rhythm. R

This orexigenic effect by phoenixin has also shown to reduce body temperature in animal models. R

Low phoenixin levels may contribute to reduced feeding and anxiety in anorexia (e.g. obese men: ~0.68ng/ml; anorexic young adults: ~0.31ng/ml). R R R

4. May Reduce Pain

Phoenixin affects pain perception. R R

In animal models of inducing pain, phoenixin can reduce visceral pain but increase itching. R R

This is because phoenixin induces sensations of itch (via release of dynorphin which inhibits spinal inhibitory glycine/gamma-aminobutyric acid neurons in a kappa opioid-dependent fashion leading to a disinhibition of spinal neurons). R R

Phoenixin may also work with GnRH to reduce inflammation. R

5. May Improve Cognitive Impairment

Phoenixin levels may negatively correlate with cognitive impairment: higher levels of phoenixin may be better for memory recall, but worse for logical memory. R

For example, patients with subjective memory complaints who had higher levels of Phoenixin have better immediate recall scores (on the Rey Auditory Verbal Learning Word List test). R

 In another study with animals, phoenixin was able to enhance memory and mitigate memory impairment induced by amyloid beta and scopolamine. R

In these studies, the effect of phoenixin on cognition lasted days after treatment. R

On the other hand, patients with mild cognitive impairment (MCI), and mild Alzheimer's disease (AD) had shown to have higher levels of phoenixin, as well as higher systolic blood pressure, which may be contributing to vascular dementia. R

6. Combats Vascular Disease

Phoenixin has cardioprotective effects on the cardiovascular system. 

For example, rats fed a high fat diet (thus increased phoenixin) did not have obesity-related cardiovascular malfunction. R

In rodent models of a heart attack, phoenixin can reduce damage to the heart, while restoring blood flow to the heart restores cardiac phoenixin levels. R

Phoenixin can promote healthy left ventricular pressure (LVP) enhance proper nitric oxide (NO) vascular relaxation (increases eNOS/pkb/erk 1/2) and normalize blood pressure. R

1. May Worsen Wound Healing

GPR173 also may play a role in wound healing.

For example, by binding to GPR173, it can inhibit migration of cells, thereby prolonging wound healing and modulating neuronal migration during development. R R

2. May Be Implicated In Cancer

GPR173 in combination with NTK1 or ALK has been a target for specific immunotherapies treating brain cancer. R

3. May Contribute To PCOS

Phoenixin levels may contribute to Polycystic Ovarian Syndrome (PCOS) in women. R

For example, phoenixin levels are found to be higher in women with PCOS, as well as higher levels of LH, FSH, TT, P4, BMI and nesfatin-1, and lower levels of E2 and insulin. R

4. Increases Weight Gain

Higher levels of phoenixin are seen in patients with high BMI. R R

• Estrogen (estradiol) in young R

• Cetrorelix (GnRH receptor antagonist) R
• Estrogen (estradiol) in elderly R
• High fat diet - causes desensitization of phoenixin signalling R

Simple:

• Increases AVP (no effect on oxytocin) R
• Increases cAMP-PKA R
• Increases CREB R
• Increases Dynorphin R
• Increases eNOS R
• Increases ERK1/2 R R
• Increases GnRH (with -14 initially then caused a decrease below control after ~30 min) R
• Increases Kisspeptin R
• Increases Nesfatin-1 R
• Increases LH (with -20 LH increases at 5 and 15 min in female animal models) R
• Increases PKB R
• Increases SON R
• Reduces Bax R
• Reduces Caspase 3 R
• Reduces Cytochrome C R
• Reduces C/EBP R 
• Reduces Oct-1 R
• Reduces p38 R

Advanced:

• Both phoenixin-14 and -20 significantly augment luteinizing hormone (LH) release, although -20 is effective at a lower concentration. R
• In order to stimulate GnRH, phoenixin decreases C/EBP mRNA and increases Oct-1 (octamer transcription factor-1), while stimulating cAMP levels and the phosphorylation of CREB (cAMP response element binding protein) and Erk 1/2, and acts by intracellular signaling of the cAMP-PKA (protein kinase A) pathway. R
• Phoenixin (undiscovered) may also act on complex IV or COX1 from SMIM20/MITRAC7. R
• GPR173 is widely distributed, especially in the brain, ovary and small intestine, co-localizing with the expression of GPR27 and GRP85 and highly expressed in areas with a high degree of plasticity such as the SON and PVN, hippocampal formation and olfactory system, suggesting implications in neural plasticity of the SREB family. R R

• In the rat hypothalamus 70–86% of phoenixin-immunoreactive cells colocalize with nesfatin-1. R

SMIM20/MITRAC7

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• Genetics of RA susceptibility, what comes next? R
• Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells R