Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood–brain barrier and directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Romere, C. et al. Asprosin, a fasting-induced glucogenic protein hormone. Cell 165, 566–579 (2016).
O'Neill, B., Simha, V., Kotha, V. & Garg, A. Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome. Am. J. Med. Genet. A. 143A, 1421–1430 (2007).
Jacquinet, A. et al. Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3′ end of FBN1 gene. Eur. J. Med. Genet. 57, 230–234 (2014).
Judge, D.P. & Dietz, H.C. Marfan's syndrome. Lancet 366, 1965–1976 (2005).
Even, P.C. & Nadkarni, N.A. Indirect calorimetry in laboratory mice and rats: principles, practical considerations, interpretation and perspectives. Am. J. Physiol. Regul. Integr. Comp. Physiol. 303, R459–R476 (2012).
Aponte, Y., Atasoy, D. & Sternson, S.M. AgRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14, 351–355 (2011).
Krashes, M.J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).
Luquet, S., Perez, F.A., Hnasko, T.S. & Palmiter, R.D. NPY–AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005).
Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001).
Denis, R.G.P. et al. Palatability can drive feeding independent of AgRP neurons. Cell Metab. 22, 646–657 (2015).
Atasoy, D., Betley, J.N., Su, H.H. & Sternson, S.M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).
Tong, Q., Ye, C.-P., Jones, J.E., Elmquist, J.K. & Lowell, B.B. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat. Neurosci. 11, 998–1000 (2008).
Garfield, A.S. et al. A neural basis for melanocortin-4 receptor–regulated appetite. Nat. Neurosci. 18, 863–871 (2015).
Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J. & Cone, R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).
Nakajima, K. et al. Gs-coupled GPCR signaling in AgRP neurons triggers sustained increase in food intake. Nat. Commun. 7, 10268 (2016).
Trumbo, P., Schlicker, S., Yates, A.A. & Poos, M. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J. Am. Diet. Assoc. 102, 1621–1630 (2002).
Butte, N.F., Wong, W.W. & Hopkinson, J.M. Energy requirements of lactating women derived from doubly labeled water and milk energy output. J. Nutr. 131, 53–58 (2001).
Roberts, S.B. Use of the doubly labeled water method for measurement of energy expenditure, total body water, water intake, and metabolizable energy intake in humans and small animals. Can. J. Physiol. Pharmacol. 67, 1190–1198 (1989).
Schoeller, D.A. Measurement of energy expenditure in free-living humans by using doubly labeled water. J. Nutr. 118, 1278–1289 (1988).
Johnson, R.K., Driscoll, P. & Goran, M.I. Comparison of multiple-pass 24-hour recall estimates of energy intake with total energy expenditure determined by the doubly labeled water method in young children. J. Am. Diet. Assoc. 96, 1140–1144 (1996).
National Research Council. Guide for the Care and Use of Laboratory Animals 8th edn. (The National Academies Press, 2011).
Luquet, S., Perez, F., Hnasko, T. & Palmiter, R. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005).
Bae, S., Park, J. & Kim, J.S. Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases. Bioinformatics 30, 1473–1475 (2014).
Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).
Berglund, E.D. et al. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J. Clin. Invest. 123, 5061–5070 (2013).
Cao, X. et al. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice. J. Clin. Invest. 124, 4351–4362 (2014).
Xu, P. et al. Activation of serotonin 2C receptors in dopamine neurons inhibits binge-like eating in mice. Biol. Psychiatry 81, 737–747 (2017).
Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).
Ren, H. et al. FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149, 1314–1326 (2012).
Sohn, J.-W. et al. Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. Cell 152, 612–619 (2013).
Liu, Y. et al. Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat. Protoc. 8, 1670–1679 (2013).
Liu, T. et al. Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73, 511–522 (2012).
Yan, C. et al. Apolipoprotein A-IV inhibits AgRP–NPY neurons and activates pro-opiomelanocortin neurons in the arcuate nucleus. Neuroendocrinology 103, 476–488 (2016).
This work was supported in part by the Baylor College of Medicine Mouse Metabolism Core (funded by NIH grant P30 DK079638), the Protein and Monoclonal Antibody Production Core (funded by NIH grant P30 CA125123), and the Mouse Phenotyping Core (funded by NIH grant UM1HG006348). Mammalian asprosin was provided by the University of North Carolina at Chapel Hill Protein Expression and Purification Core (funded by NIH grant P30 CA016086). Support was also provided by American Heart Association postdoctoral fellowships 16POST29630010 (C.D.) and 16POST27260254 (C.W.), the American Diabetes Association (grants 1-17-PDF-138 (Y.H.) and 1-17-JDF-009 (K.J.P.)), the NIDDK (grants 1R01DK111631 (K.J.P.), DK075087 (M.J.K.), DK101379 (Y.X.), and 1K08DK102529 (A.R.C.)), the NLM (grant LM012806; Z.Z.), the NHGRI Baylor–Johns Hopkins Center for Mendelian Genomics (grant UM1 HG006542; V.R.S.), the R.P. Doherty, Jr. –Welch Chair in Science Q-0022 (D.D.M.), the Intramural Research Program of the NIH (M.J.K.), and the USDA–CRIS (3092-5-001-059; Y.X.). A.R.C. is also supported by the Chao Physician-scientist Award, the Caroline Wiess Law scholar award, and a departmental laboratory startup package.
The authors declare no competing financial interests.
About this article
Cite this article
Duerrschmid, C., He, Y., Wang, C. et al. Asprosin is a centrally acting orexigenic hormone. Nat Med 23, 1444–1453 (2017). https://doi.org/10.1038/nm.4432
Neuropathology and Applied Neurobiology (2021)
The effect of combined resistance aerobic exercise training on concentrations of asprosin and complement C1q tumor necrosis factor-related protein-1 in men with type 2 diabetes
Sport Sciences for Health (2021)
International Journal of Molecular Sciences (2021)
Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity (2021)