Asprosin, a Novel Member in Glucose Regulatory Family

王雪瑩

1. Introduction

Adipose tissue， a central endocrinal organ， recently has been given lots of insight into the scientific community. Novel adipokines were identified from white， brown and beige adipocytes. Two years ago， a peptide hormone was identified by Chopra and his colleagues named asprosin. It is a fasting-induced signaling molecule enriched by white adipose tissue （WAT）， targeting at liver cells and rapidly stimulating hepatic glucose release as well as causing compensatory insulin increase. Further research found that this hormone can also cross blood-brain barrier and directly activate Satiety center in the hypothalamus. This suggests a potential therapeutic approach using an asprosin-specific monoclonal antibody to control blood glucose level for treating diseases like type 2 diabetes mellitus （T2DM） and obesity. Asprosin has similar mechanisms as other appetite-controling hormones like ghrelin and leptin.

2. History of discovery

Asprosin was initially discovered in patients who suffer from neonatal progeroid syndrome （NPS）， an autosomal recessive disease with syndromes of adipose loss particularly in face and limbs. Researchers found that all of the NPS patients displayed a lower insulin level than normal people. Furthermore， a heterozygous 30bp truncating mutations in the gene FBN1 was identified in all cases which limit the expression of this gene. FBN1 encodes for the protein profibrillin. It was suggested that there might be some associations between profibrillin and insulin regulation. As a proprotein， profibrillin is cleavaged by protease furin at Carboxyl-terminus. This modified polypeptide can be detected in the circulatory system， where it plays a role in blood glucose and insulin regulation. Therefore， it is defined as a novel hormone.

3. Asprosin targets the metabolism in the liver

Asprosin is targeting a specific process in the liver. Researchers found that a single dose of injected asprosin can boost blood glucose immediately. This resulted in a compensatory increase of insulin that regulates blood glucose to a normal level. It has been shown that the surface of livers has specific G protein coupled receptors （GPCRs） for asprosin to bind. When it binds to the receptor， a Gs protein-cAMP-Protein kinase A （PKA） axis is employed. PKA carries on a cascade of phosphorylation reactions. In turn， glycogen degradation switches on and synthesis turns off. Also， gluconeogenesis switches on. Eventually the blood glucose level is upregulated. The higher levels of blood glucose will be detected， thereby more insulin is released from isletβcells. Up-regulated insulin will further act on liver to reduce glucose and maintain it at a general level. This regulation can sustain normal blood glucose balance at a fasting condition.

4. Asprosin has a targeting receptor in the hypothalamus

The second targeting receptors are in the hypothalamus. After discovering the novel hormone， Chopras group were interested in a common syndrome existed in NPS individuals - patients display anorexia and weight loss. It seemed that asprosin may also participate in the appetite regulation. They found circulating asprosin could go through blood brain barrier （BBB） and entered the cerebrospinal fluid （CSF）， essentially acting on a specific type of neurons within the arcuate nucleus of the hypothalamus. This type of neurons， with an expression of agouti-related protein （AgRP）， can sense any orexigenic factors as well as orchestrate a starving behavior. Milestone in clinical application

（1） Blocking agent to treat T2DM

It was revealed that patients with insulin resistance displayed higher levels of asprosin than healthy people. Chopra and his colleagues tested an asprosin-specific monoclonal antibody in insulin-resistant mouse models. The result showed plasma asprosin levels were reduced and insulin sensitivities were improved. This finding confirmed that immunologic sequestration of asprosin as a feasible way to treat T2DM. A clinical trial in humans might be launched within a couple of years.

（2） Supplement for NPS rescue

Experiment showed that the hypophagia symptom can be relieved by subcutaneously injecting a single dose of asprosin in mice， which demonstrated that NPS was directly caused by asprosin insufficiency instead of other factors from FBN1 mutation. Therefore recombinant asprosin administration is a potent and convenient way to take NPS under control.

（3） Blocking agent to treat obesity

Considering the second target， immunological neutralization of asprosin should be a potential method to decrease appetite and body weight. Chopra and his colleagues inhibited asprosin functions by pharmacologically injected specific antibodies to another mice model. Successfully， it diminished appetite and led to continuous weight loss.

5. Conclusion

Asprosin was discovered from a rare disease named NPS. In fasting condition， it targets on liver cells to activate a Gs protein-cAMP-Protein PKA axis， which boosts blood glucose immediately and gradually normalize it as well as increase insulin level. Because of the pathologically elevated level of asprosin in insulin resistant individuals， blocking antibodies might be an alternative way to treat T2DM. This idea received desired effect in mouse models and will be prepared for trials in human. This hormone can also go across BBB， stimulating AgRP neurons as well as inhibiting POMC neurons in arcuate area of hypothalamus. Finally it triggers an orexigenic effects. Blocking of this pathway may be considered as an efficient way for obesity therapies. Nowadays， more and more scientists attach importance to this field， trying to find the structures， generating pathway， receptor and more clinical usages of asprosin. Hopefully， it can bring benefit to mankind as soon as possible.

作者簡介：王雪瑩（1998—），女，漢，山東省濱州市，本科在讀，南昌大學瑪麗女王學院，臨床醫學和生物醫學專業