Asprosin

Asprosin is a protein hormone produced by mammals in (white adipose) tissues that stimulates the liver to release glucose into the blood stream. Asprosin is encoded by the gene FBN1 as part of the protein profibrillin and is released from the C-terminus of the latter by specific proteolysis. In the liver, asprosin activates rapid glucose release via a cyclic adenosine monophosphate (cAMP)-dependent pathway.[1]

Fibrillin 1
Identifiers
SymbolFBN1
NCBI gene2200
HGNC3603
OMIM134797
RefSeqNP_000129
UniProtP35555
Other data
LocusChr. 15 q21.1

Discovery

Asprosin was first identified by Dr. Atul Chopra and coworkers at Baylor College of Medicine as a C-terminal cleavage product of the FBN1 gene product profibrillin. They found mutations in the FBN1 gene in two patients with congenital partial lipodystrophy and a progeroid appearance.[1][2] The two patients were Lizzie Velasquez and Abby Solomon.[3][4] Truncations of the FBN1 protein in these patients were seen to have two consequences for protein production: a mutant/truncated fibrillin protein and very low plasma asprosin levels (from a postulated dominant negative effect).[1][5][6] The condition has since been named Marfanoid–progeroid–lipodystrophy syndrome.

Function

The liver stores excess glucose in the form of glycogen after a meal, in response to insulin. Between meals (or during fasting), the liver is stimulated to break down this glycogen to release glucose (glycogenolysis) and also synthesizes new glucose (gluconeogenesis); this glucose is released into the bloodstream to maintain normal function of the brain and other organs that burn glucose for energy. Glycogenolysis and gluconeogenesis are stimulated by hormones such as glucagon that activate the cyclic AMP pathway in liver hepatocytes, and this cAMP promotes activation of metabolic enzymes leading to glucose production and release; asprosin appears to utilize this same system of control.[7][8]

Asprosin was reported to stimulate glucose release from hepatocytes, and plasma levels of asprosin in obese high-fat-fed mice have been reported to nearly double.[1] However, in a study in 2019, a pharma replication group reported their inability to replicate these two key observations using multiple forms of recombinant asprosin, suggesting that issues with reagent purity may have been responsible for the effect observed in the initial asprosin study.[9] Nevertheless, a third group reported in 2019 that they had identified the receptor for asprosin, an olfactory receptor family GPCR expressed on liver hepatocytes, and showed that plasma asprosin levels increased with fasting and high fat diet, and that asprosin stimulated glucose release in normal mice (thereby confirming the original study) but that mice lacking this receptor were unable to respond to asprosin by releasing glucose.[10]

Clinical significance

Fibrillin-1 is important for the formation of elastic fibers in connective tissues, and patients with mutations in FBN1 gene exhibit Marfan syndrome.[11] Individuals with Marfanoid–progeroid–lipodystrophy syndrome (MPL) are deficient in asprosin due to mutations affecting the carboxy terminus of the profibrillin-1 protein and its processing into fibrillin-1 and asprosin.[1][12]

Therapeutic potential

Patients presenting with insulin resistance and obesity have elevated serum levels of asprosin,[1] and female patients with polycystic ovary syndrome have particularly high serum levels.[13] Obese patients undergoing bariatric surgery for weight loss show decreased asprosin levels in serum after surgery [14]

In a test of pharmacologic asprosin depletion in animals, preliminary results raised the possibility of its use, therapeutically, in treating type 2 diabetes and obesity.[15] For instance, Chopra and coworkers observed that when antibodies targeting asprosin were injected into diabetic mice, blood glucose and insulin levels improved.[1][5]

Asprosin has also been reported to cross the blood-brain barrier to regulate neurons in the hypothalamus of the brain known to regulate hunger and satiety, and inhibiting asprosin in obese mice reduced feeding and led to decreased body weight.[2][16]

References

  1. Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, et al. (April 2016). "Asprosin, a Fasting-Induced Glucogenic Protein Hormone". Cell. 165 (3): 566–79. doi:10.1016/j.cell.2016.02.063. PMC 4852710. PMID 27087445.
  2. Duerrschmid C, He Y, Wang C, Li C, Bournat JC, Romere C, et al. (December 2017). "Asprosin is a centrally acting orexigenic hormone". Nature Medicine. 23 (12): 1444–1453. doi:10.1038/nm.4432. PMC 5720914. PMID 29106398.
  3. Kennedy, Pagan (25 Nov 2016). "The Thin Gene". The New York Times. Retrieved 22 May 2017.
  4. Bordo, Sara (Director); Campo, Michael (Writer); Velasquez, Lizzie (Star) (2015). A Brave Heart: The Lizzie Velasquez Story. Event occurs at 45:50 to 50:36.
  5. Pathak, Dipali (Apr 14, 2016). "Discovery of Asprosin, New Hormone Could Have Potential Implications in Treatment of Diabetes". Houston, TX: Baylor College of Medicine. Retrieved 18 April 2016.
  6. Coghlan A (14 April 2016). "Newly discovered hormone could fight type 2 diabetes and obesity". New Scientist. Retrieved 20 April 2016.
  7. Levine R (1986). "Monosaccharides in health and disease". Annual Review of Nutrition. 6: 211–24. doi:10.1146/annurev.nu.06.070186.001235. PMID 3524617.
  8. Röder PV, Wu B, Liu Y, Han W (March 2016). "Pancreatic regulation of glucose homeostasis". Experimental & Molecular Medicine. 48 (3, March): e219. doi:10.1038/emm.2016.6. PMC 4892884. PMID 26964835.
  9. von Herrath M, Pagni PP, Grove K, Christoffersson G, Tang-Christensen M, Karlsen AE, Petersen JS (April 2019). "Case Reports of Pre-clinical Replication Studies in Metabolism and Diabetes". Cell Metabolism. 29 (4): 795–802. doi:10.1016/j.cmet.2019.02.004. PMID 30879984.
  10. Li E, Shan H, Chen L, Long A, Zhang Y, Liu Y, et al. (June 2019). "OLFR734 Mediates Glucose Metabolism as a Receptor of Asprosin". Cell Metabolism. 30 (2): 319–328.e8. doi:10.1016/j.cmet.2019.05.022. PMID 31230984.
  11. "What Is Marfan Syndrome?". NHLBI, NIH. October 1, 2010. Archived from the original on 6 May 2016. Retrieved 16 May 2016.
  12. Grens K (April 15, 2016). "Newly Discovered Hormone Explains Disease". The Scientist. Retrieved 18 April 2016.
  13. Alan M, Gurlek B, Yilmaz A, Aksit M, Aslanipour B, Gulhan I, et al. (March 2019). "Asprosin: a novel peptide hormone related to insulin resistance in women with polycystic ovary syndrome". Gynecological Endocrinology. 35 (3): 220–223. doi:10.1080/09513590.2018.1512967. PMID 30325247. S2CID 53290102.
  14. Wang CY, Lin TA, Liu KH, Liao CH, Liu YY, Wu VC, et al. (May 2019). "Serum asprosin levels and bariatric surgery outcomes in obese adults". International Journal of Obesity. 43 (5): 1019–1025. doi:10.1038/s41366-018-0248-1. PMID 30459402. S2CID 53872918.
  15. Greenhill C (June 2016). "Liver: Asprosin - new hormone involved in hepatic glucose release". Nature Reviews. Endocrinology. 12 (6): 312. doi:10.1038/nrendo.2016.66. PMID 27125501. S2CID 37629594.
  16. Beutler LR, Knight ZA (February 2018). "A Spotlight on Appetite". Neuron. 97 (4): 739–741. doi:10.1016/j.neuron.2018.01.050. PMC 5965268. PMID 29470967.

Further reading

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