Asprosin

Last updated
Fibrillin 1
Identifiers
Symbol FBN1
NCBI gene 2200
HGNC 3603
OMIM 134797
RefSeq NP_000129
UniProt P35555
Other data
Locus Chr. 15 q21.1
Search for
Structures Swiss-model
Domains InterPro

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]

Contents

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 or neonatal progeroid syndrome (NPS). [7]

Profibrillin cleavage and asprosin secretion

The asprosin mechanism begins with the cleavage of profibrillin. While the specific cellular location of profibrillin cleavage is largely unknown, it is speculated to occur between the trans-Golgi network and the cell surface, or upon fibrillin-1 secretion. Furin cleaves asprosin at the R-C-K/R-R motif in the C-terminal domain. This cleavage event is important because it is required for the incorporation of fibrillin-1 into the extracellular matrix. Since furin is expressed in a plethora of cell lines and tissues, the presence or lack of this enzyme does not narrow down the possible locations of asprosin secretion.

Evidence suggests that asprosin is secreted from white adipose tissue, which accounts for 5–50% of human body weight and is already known to secrete adipokines such as leptin and adiponectin. While FBN1 is expressed in many tissues, its highest expression in both humans and mice is in white adipose. However, since FBN1 (and thus, asprosin) is widely expressed in many human tissues, it is likely that white adipose is not the only source of plasma asprosin. There has been evidence connecting asprosin secretion from wild-type human dermal fibroblasts suggesting that it may be secreted from skin. [1] It was also discovered that MIN6 pancreatic β-cells and human primary islets containing β-cells secrete asprosin and that secretion is induced by palmitate in a dose-dependent manner. [8] Asprosin has also been detected in saliva samples.

Function

Once in the circulation, asprosin targets the liver and the brain.

Function in liver

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. [9] [10]

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. [11] 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. [12] The liver receptor for asprosin is OR4M1. Three additional studies have since confirmed asprosin's glucogenic function. [13] [14] [15]

Function in brain

Asprosin can also exit the bloodstream and cross the blood–brain barrier to function in the brain. The first indication that asprosin was in fact a cerebrospinal fluid (CSF) protein, in addition to being a plasma protein, was the observation of asprosin in the CSF of rats at concentrations 5- to 10-fold lower than in the plasma. Additionally, intravenously introduced asprosin showed a dramatic ability to cross the blood–brain barrier and enter the CSF. [2]

A central mechanism of appetite regulation is via orexigenic AgRP neurons and anorexigenic POMC neurons in the arcuate nucleus of the hypothalamus. Asprosin directly activates orexigenic AgRP neurons and, using the neurotransmitter GABA, indirectly inhibits anorexigenic POMC neurons. [2]

Asprosin’s orexigenic effects are mediated through binding to protein tyrosine phosphatase receptor delta (PTPRD). [16] Genetic ablation of PTPRD results in extreme leanness and loss of appetite. More specifically, resistance to diet-induced obesity can occur through the loss of PTPRD in AgRP neurons.  When asprosin binds to PTPRD, this leads to the de-phosphorylation and de-activation of Stat3. PTPRD is highly expressed throughout the entire brain, especially in the cerebellum and cerebellar hemisphere. PTPRD is also highly expressed in the coronary arteries, the aorta, and the ovaries.

Classification

Asprosin is a protein hormone, but is unique in its generation as the C-terminal cleavage product of a large extracellular matrix protein. Therefore, it has been postulated to belong to a new protein hormone subclass: caudamins. It has been placed in this subclass along with the hormones: endostatin, endotrophin and placensin. [17] Members of this class are derived from a cleavage event that also generates a much larger, functionally unrelated, nonhormonal protein. The subclass was named caudamins, from the Latin word cauda meaning 'tail'.

Clinical significance

Asprosin

Obesity is characterized by an overall increase in adiposity and, given that asprosin is secreted by adipose tissue, it is not surprising that both obese humans and mice show pathologically elevated levels of asprosin compared with control subjects. 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. [18] Obese patients undergoing bariatric surgery for weight loss show decreased asprosin levels in serum after surgery. [19]

Asprosin-induced hyperphagia and hepatic glucose production could therefore be mechanisms that drive development of metabolic syndrome. [20]

Fibrillin-1

Fibrillin-1 is important for the formation of elastic fibers in connective tissues, and patients with mutations in FBN1 gene exhibit Marfan syndrome. [21] 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] [22]

Therapeutic potential

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. [23] For instance, Chopra and coworkers observed that when antibodies targeting asprosin were injected into diabetic mice, blood glucose and insulin levels improved. [1] [5]

Monoclonal anti-asprosin antibody

Mishra and colleagues have demonstrated that anti-asprosin mAbs (monoclonal antibody) are a dual-effect therapy that targets the two key pillars of metabolic syndrome – overnutrition and plasma glucose burden . Specifically, anti-asprosin mAbs have been shown to reduce blood glucose, appetite, and body weight in various environmental and genetic models of metabolic syndrome. These findings have led to an effort to optimize and develop clinical-grade anti-asprosin mAbs for use in humans. [24]

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] [25]

Related Research Articles

<span class="mw-page-title-main">Metabolic syndrome</span> Medical condition

Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy, is used when describing the loss of fat from one area. This condition is also characterized by a lack of circulating leptin which may lead to osteosclerosis. The absence of fat tissue is associated with insulin resistance, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor</span> Group of nuclear receptor proteins

In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

11β-Hydroxysteroid dehydrogenase enzymes catalyze the conversion of inert 11 keto-products (cortisone) to active cortisol, or vice versa, thus regulating the access of glucocorticoids to the steroid receptors.

Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

Nesfatin-1 is a neuropeptide produced in the hypothalamus of mammals. It participates in the regulation of hunger and fat storage. Increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a 'sense of fullness', and a potential loss of body fat and weight.

<span class="mw-page-title-main">Blood sugar regulation</span> Hormones regulating blood sugar levels

Blood sugar regulation is the process by which the levels of blood sugar, the common name for glucose dissolved in blood plasma, are maintained by the body within a narrow range.

<span class="mw-page-title-main">White adipose tissue</span> Fatty tissue composed of white adipocytes

White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.

<span class="mw-page-title-main">Fatty acid-binding protein</span>

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<span class="mw-page-title-main">Fibrillin-1</span> Protein-coding gene in the species Homo sapiens

Fibrillin-1 is a protein that in humans is encoded by the FBN1 gene, located on chromosome 15. It is a large, extracellular matrix glycoprotein that serves as a structural component of 10-12 nm calcium-binding microfibrils. These microfibrils provide force bearing structural support in elastic and nonelastic connective tissue throughout the body. Mutations altering the protein can result in a variety of phenotypic effects differing widely in their severity, including fetal death, developmental problems, Marfan syndrome or in some cases Weill-Marchesani syndrome.

<span class="mw-page-title-main">NRIP1</span> Protein-coding gene in the species Homo sapiens

Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a protein that in humans is encoded by the NRIP1 gene.

<span class="mw-page-title-main">Free fatty acid receptor 1</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded by the FFAR1 gene. This gene is located on the short arm of chromosome 19 at position 13.12. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2, FFAR3, and FFAR4. FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">PTPRD</span> Protein-coding gene in humans

Receptor-type tyrosine-protein phosphatase delta is an enzyme that, in humans, is encoded by the PTPRD gene.

<span class="mw-page-title-main">Chemerin</span> Protein-coding gene in the species Homo sapiens

Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.

<span class="mw-page-title-main">Wiedemann–Rautenstrauch syndrome</span> Medical condition

Wiedemann–Rautenstrauch (WR) syndrome, also known as neonatal progeroid syndrome, is a rare autosomal recessive progeroid syndrome. There have been over 30 cases of WR. WR is associated with abnormalities in bone maturation, and lipids and hormone metabolism.

<span class="mw-page-title-main">Marfanoid–progeroid–lipodystrophy syndrome</span> Medical condition

Marfanoid–progeroid–lipodystrophy syndrome (MPL), also known as Marfan lipodystrophy syndrome (MFLS) or progeroid fibrillinopathy, is an extremely rare medical condition which manifests as a variety of symptoms including those usually associated with Marfan syndrome, an appearance resembling that seen in neonatal progeroid syndrome, and severe partial lipodystrophy. It is a genetic condition that is caused by mutations in the FBN1 gene, which encodes profibrillin, and affects the cleavage products of profibrillin, fibrillin-1, a fibrous structural protein, and asprosin, a glucogenic protein hormone. As of 2016, fewer than 10 cases of the condition have been reported. Lizzie Velásquez and Abby Solomon have become known publicly through the media for having the condition.

Hepatokines are proteins produced by liver cells (hepatocytes) that are secreted into the circulation and function as hormones across the organism. Research is mostly focused on hepatokines that play a role in the regulation of metabolic diseases such as diabetes and fatty liver and include: Adropin, ANGPTL4, Fetuin-A, Fetuin-B, FGF-21, Hepassocin, LECT2, RBP4,Selenoprotein P, Sex hormone-binding globulin.

References

  1. 1 2 3 4 5 6 7 8 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): 566–579. doi:10.1016/j.cell.2016.02.063. PMC   4852710 . PMID   27087445.
  2. 1 2 3 4 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 P (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. 1 2 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. ↑ "Neonatal progeroid syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2021-10-27. Retrieved 2021-10-25.
  8. ↑ Lee T, Yun S, Jeong JH, Jung TW (April 2019). "Asprosin impairs insulin secretion in response to glucose and viability through TLR4/JNK-mediated inflammation". Molecular and Cellular Endocrinology. 486: 96–104. doi:10.1016/j.mce.2019.03.001. PMID   30853600. S2CID   72334358.
  9. ↑ Levine R (1986). "Monosaccharides in health and disease". Annual Review of Nutrition. 6: 211–224. doi:10.1146/annurev.nu.06.070186.001235. PMID   3524617.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Li E, Shan H, Chen L, Long A, Zhang Y, Liu Y, et al. (August 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.
  13. ↑ Yu Y, He JH, Hu LL, Jiang LL, Fang L, Yao GD, et al. (June 2020). "Placensin is a glucogenic hormone secreted by human placenta". EMBO Reports. 21 (6): e49530. doi:10.15252/embr.201949530. PMC   7271319 . PMID   32329225.
  14. ↑ Zhang Y, Zhu Z, Zhai W, Bi Y, Yin Y, Zhang W (March 2021). "Expression and purification of asprosin in Pichia pastoris and investigation of its increase glucose uptake activity in skeletal muscle through activation of AMPK". Enzyme and Microbial Technology. 144: 109737. doi:10.1016/j.enzmictec.2020.109737. PMID   33541572. S2CID   231818554.
  15. ↑ Hekim MG, Kelestemur MM, Bulmus FG, Bilgin B, Bulut F, Gokdere E, et al. (March 2021). "Asprosin, a novel glucogenic adipokine: a potential therapeutic implication in diabetes mellitus". Archives of Physiology and Biochemistry. 129 (5): 1038–1044. doi:10.1080/13813455.2021.1894178. PMID   33663304. S2CID   232122209.
  16. ↑ Mishra I, Xie WR, Bournat JC, He Y, Wang C, Silva ES, et al. (April 2022). "Protein tyrosine phosphatase receptor δ serves as the orexigenic asprosin receptor". Cell Metabolism. 34 (4): 549–563.e8. doi:10.1016/j.cmet.2022.02.012. PMC   8986618 . PMID   35298903.
  17. ↑ Basu B, Jain M, Chopra AR (December 2021). "Caudamins, a new subclass of protein hormones". Trends in Endocrinology and Metabolism. 32 (12): 1007–1014. doi:10.1016/j.tem.2021.09.005. PMC   8585694 . PMID   34666940. S2CID   238996604.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ Yuan M, Li W, Zhu Y, Yu B, Wu J (2020). "Asprosin: A Novel Player in Metabolic Diseases". Frontiers in Endocrinology. 11: 64. doi: 10.3389/fendo.2020.00064 . PMC   7045041 . PMID   32153505.
  21. ↑ "What Is Marfan Syndrome?". NHLBI, NIH. October 1, 2010. Archived from the original on 6 May 2016. Retrieved 16 May 2016.
  22. ↑ Grens K (April 15, 2016). "Newly Discovered Hormone Explains Disease". The Scientist . Retrieved 18 April 2016.
  23. ↑ 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.
  24. ↑ Mishra I, Duerrschmid C, Ku Z, He Y, Xie W, Silva ES, et al. (April 2021). Isales M, Zaidi C, Isales C (eds.). "Asprosin-neutralizing antibodies as a treatment for metabolic syndrome". eLife. 10: e63784. doi: 10.7554/eLife.63784 . PMC   8102062 . PMID   33904407.
  25. ↑ 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.

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