Inverse exerkine. Circulating levels fall with exercise: lower levels reflect health, while elevated levels cause insulin and exercise resistance.
Definition
- Selenoprotein P is a major plasma selenoprotein containing selenocysteine residues PMID 37258587
- Selenoprotein P (SeP; encoded by Selenop in mice) is a hepatokine PMID 36947851
Biological function
- Selenoprotein P has a physiological and nutritional role as a selenium transporter and antioxidant due to its capacity to reduce phospholipid hydroperoxide PMID 37258587
- SeP causes insulin resistance in hepatocytes and myocytes by several mechanisms, including suppressing auto-phosphorylation of insulin receptor, AKT pathways responding to insulin, decreasing insulin-induced cellular glucose uptake, suppressing the hepatic AMPK signaling pathways, and by disrupting insulin production by pancreatic beta cells PMID 37258587
- In the skeletal muscle, SeP causes exercise and insulin resistance by inactivating the exercise-mediated AMP-activated protein kinase PMID 36947851
- Sepp1 deficiency downregulates EV biogenesis machinery, accompanied by increased lysosomal activity and lipid metabolism PMID 39616613
- Downregulation of Sepp1 impacts endolysosomal pathways and disrupts intraluminal vesicle biogenesis PMID 39616613
Exerkine classification
- Exercise training modulates the levels of different organokines, including adipokines, myokines and hepatokines (38) and exercise induced changes in hepatokine levels have been suggested to ameliorate metabolic disorders such as obesity or T2D PMID 37258587
- Performing 12 weeks of physical activity led to decreases in selenoprotein P PMID 37258587
- In the skeletal muscle, SeP causes exercise and insulin resistance by inactivating the exercise-mediated AMP-activated protein kinase PMID 36947851
Therapeutic potential
- Excess selenoprotein P concentrations have been implicated in the etiology of type 2 diabetes, pulmonary hypertension non-alcoholic fatty liver disease, and other conditions PMID 37258587
- Therefore, understanding the interplay between SeP, insulin resistance, and liver function provides key insights into the pathophysiology of metabolic disorders and highlights SeP as a potential biomarker and therapeutic target PMID 37258587
- These findings suggest that SeP-mediated reductive stress is involved in and may be a therapeutic target for physical inactivity-mediated muscle atrophy PMID 36947851
- Given that it is overproduced from the liver in diabetes, SeP may be a therapeutic target against diabetes-associated sarcopenia PMID 36947851
- Sepp1 is thus an emerging therapeutic target for ameliorating microglia-mediated disease spread through EV secretion in neurodegenerative disorders. PMID 39616613
Evidence
256PubMed publications, last 5 years#30 of 35
15%Mention “therapeutic” or “therapy”38 publications
29Registered clinical trials#29 of 35
3Active or recruiting trials
Therapeutic mentionOther
Phase 1 · 2Phase 2 · 1Phase 3 · 5Phase 4 · 1Not applicable · 13
PubMed and ClinicalTrials.gov, snapshot of February 2026. Counts are keyword-based and include every study that mentions SeP. Compare across exerkines →
References 3
Primary literature cited in this profile. Each identifier opens the article on PubMed.