Asprosin, a Fasting-Induced Glucogenic Protein Hormone
Authors: Petra Constable
Dianna M Milewicz
Bokai Zhu
Joseph S Coselli
Pradip K Saha
Clemens Duerrschmid
Brian York
Maria Del Solar
Scott A LeMaire
Nancy F Butte
Chase Romere
Poonam Sarkar
Atul R Chopra
Juan Bournat
M Waleed Gaber
David D Moore
David A Rendon
Fan Xia
V Reid Sutton
Mahim Jain
Journal: Cell (2016)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Hepatic glucose release; Fasting-induced protein hormone; Asprosin; White adipose; G protein-cAMP-PKA pathway
Affiliations: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA., Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA., Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX 77030, USA., Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: .

Abstract:  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. 

Retracted: No

PubPeer comments:
 See case #2, middle column ![] , 
 This is published: https: www.sciencedirect.com science article pii S1550413119300683?via%3Dihub Please note that:  In this case we have made efforts to produce low-endotoxin, non-aggregating versions of asprosin. Despite this, we did not manage to reach the same conclusions in in vitro and in vivo function of this peptide hormone as was shown in the original publication (Romere et al., 2016). We have reached out to the authors to receive a batch of their asprosin, but this has to date not materialized. , 
 Several studies have since recapitulated, all or parts of, this original study: https: pubmed.ncbi.nlm.nih.gov 31230984 https: pubmed.ncbi.nlm.nih.gov 31798959 https: pubmed.ncbi.nlm.nih.gov 32337066 https: pubmed.ncbi.nlm.nih.gov 32329225 https: pubmed.ncbi.nlm.nih.gov 31230984 states  Of note, quality of asprosin protein is critical for its activity . Thus, seems like https: pubmed.ncbi.nlm.nih.gov 30879984 made poor quality asprosin protein and then found that it did not have activity. , 
 #3 Sure, but the cited studies are all from the same group. Moreover, are you seriously doubting the competence of Novo Nordisk in biochemistry? , 
 #4 Group 1: https: pubmed.ncbi.nlm.nih.gov 27087445 Original study on asprosin (FBN1 gene) showing its glucogenic function Group 2: https: pubmed.ncbi.nlm.nih.gov 30879984 Novo Nordisk study showing no glucogenic or orexigenic activity of in house produced recombinant asprosin Group 3: https: pubmed.ncbi.nlm.nih.gov 31230984 Discovery of hepatic asprosin receptor, reproduction of original study, explanation that quality of recombinant asprosin is critical to demonstration of its activity Group 4: https: pubmed.ncbi.nlm.nih.gov 32329225 Discovery of an asprosin-like hormone from the FBN2 gene, reproduction of original study An old mentor said, forget reputation, just follow the data. That s four independent groups of scientists. Three show asprosin activity in vitro and in vivo. One group doesn t. That s the data of this experiment. Now draw your own conclusions ;) , 
 #5 It s worth recalling the quote in #2. Novo Nordisk made a very specific effort in the preparation of their Asprosin AND the authors apparently did not supply a sample of their own special sauce. Maybe the authors could address that second point here, in public and in their own name? , 
 #6 Let s keep it to the data, rather than he said, she said :) Look, the crux of the matter is that the original findings have been confirmed and expanded upon by two other groups unconnected with each other or the original group. How would they all manage to do that if Novo s assertions were scientifically correct? , 
 It would still be useful to know from the *authors* why they would not or did not share a key reagent. As a counterweight to your  many labs argument, I suspect that before a corporation published something this controversial, they would expend very significant resources in making sure their finding was robust. Again, they are *very* pointed about the lack of help from the authors. Why wouldn t the authors share their reagent? , 
 Simple - Novo would not share their reagents so we could test them in parallel to them testing ours. We asked for them and got a blanket refusal. A collaboration should have mutual trust. This one didn t. That is no counterweight. Do you really believe corporations don t make mistakes? They made a big one in this case. Third - We ve generated several adeno and adeno-associated viruses that reliably increase plasma asprosin (in vivo gain of function) that bypass the need to use unreliable recombinant proteins altogether. We ve also generated several monoclonal antibodies against different epitopes that reliably inhibit plasma asprosin (in vivo loss of function). Both methods are easy to use, and the paper describing them is in peer review as we speak. We would be delighted to share them with any lab that wishes to study asprosin. Any takers? - Atul , 
 #9 Once you have published, surely you are supposed to facilitate replication without restriction (reasonable fees and MTAs are of course permitted)? It seems a bit naughty to leverage key reagents as a means to regulate the research of other groups, although this may not infringe Cell s weak guidelines. Novo Nordisk did the obvious, scientific thing in requesting a sample of your Asprosin in an attempt to eliminate its preparation as an explanation for the different results. You refused. You could even have tested the shared batch in parallel if you distrusted the rest of their experimental technique. Why not preprint your exciting new results? , 
 Nope, I disagree. Trust is a necessary ingredient for working with someone. You aren t going to change my mind on that. In any event, did not getting a reagent force Novo to publish wrong conclusions? A couple other groups managed to get it right without any contact with our group. Bottom line - Novo wasn t skeptical enough of their own negative results. They admitted in an email that they detected some activity in a POMC neuron electrophysiology setup. But that did not make it into their paper which gave the impression that nothing worked. It should have. Would have provided perspective that they were working with a weakly active preparation. Peer review only assesses what you put in after all. On to the future :) - Would you like our viruses and mAbs referenced above to test for yourself (applies to anyone reading this)? The viruses encode human asprosin with an IL2 signal peptide attached to induce secretion. With this technique you use the mouse liver as a factory that overexpresses and secretes human asprosin into the circulation. Sort of like a sustained release pump, without the negative of working with unreliable recombinant proteins. All viruses (adenos and AAVs) produce increase in plasma asprosin, food intake, body weight and blood glucose. Three distinct mAbs do the opposite at baseline, AND rescue the effects of the viruses. Preprint is a great idea. I am tempted to include the reviews we just got (can we do that without getting in trouble?). One reviewer liked it and the other hated it. Go figure. Either way, will do it next week. In the mean time drop me a line at atul.chopra@case.edu and I ll send you a copy of the paper and the journal reviews. Atul , 
 Here is the preprint referenced above - https: www.biorxiv.org content 10.1101 2020.09.15.298489v1 Atul ,