Asprosin

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.

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]

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]

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]

• "OMIM Entry - #616914 - MARFAN LIPODYSTROPHY SYNDROME; MFLS". omim.org. Retrieved 2016-12-06.