Asprosin, a Fasting-Induced Glucogenic Protein Hormone

Abstract

SUMMARY Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.

Regulation of hepatic glucose metabolism in health and disease

“…Phosphorylation of PFK2/FBPase-2 favours its phosphatase activity, enabling it to decrease the production of fructose-2,6-bisphosphate, an allosteric inhibitor of the gluconeogenic enzyme fructose-2,6-bisphosphatase 1 (FBPase-1) 98,99 ; phosphorylated PFK2/FBPase-2 also facilitates the nuclear translocation and consequent functional inactivation of glucokinase (GCK) 100 . These mechanisms might also underlie the stimulatory effect of asprosin (an adipose-derived peptide hormone that activates hepatocellular cAMP–PKA signalling) on HGP 101 . The observation that asprosin stimulated HGP in mice that were fasted for 18 h (REF.…”

Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

“…They showed that plasma asprosin peaks during fasting and induces HGP through the activation of cAMP-PKA pathway [220]. In addition, they reported that insulin-resistant mice and prediabetic humans displayed elevated levels of asprosin [220].…”

“…In addition, they reported that insulin-resistant mice and prediabetic humans displayed elevated levels of asprosin [220]. Blocking asprosin using an antiasprosin monoclonal antibody dampened HGP and normalized glucose and insulin levels in insulin-resistant mice [220]. …”

“…Recently, Chopra and colleagues [220] identified a new hormone, asprosin, which is secreted by WAT and acts primarily on the liver to drive glucose release. They showed that plasma asprosin peaks during fasting and induces HGP through the activation of cAMP-PKA pathway [220].…”

Advances in the understanding of adipose tissue biology

“…In 2016, Chopra and colleagues identified mutations in the gene that encodes profibrillin ( FBN1 ) in patients with NPS; the mutations were found to disrupt the expression of asprosin, the C-terminal cleavage product of profibrillin 2 . Asprosin, which is a 140-amino-acid secreted polypeptide, is abundantly expressed in mature white adipocytes and is thus considered a new adipokine.…”