Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Asprosin is a centrally acting orexigenic hormone

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Neonatal progeroid syndrome (NPS) is associated with hypophagia.
Figure 2: Introducing the NPS-associated mutation in mice results in hypophagia, reduced adiposity, and protection from diet-induced obesity.
Figure 3: Correction of the asprosin deficiency completely rescues hypophagia and the depressed activity of AgRP+ neurons in Fbn1NPS/+ mice.
Figure 4: Asprosin crosses the blood–brain barrier and stimulates appetite.
Figure 5: AgRP+ neurons are essential for asprosin-mediated appetite stimulation.
Figure 6: Immunological neutralization of asprosin is protective against obesity.

References

  1. 1

    Romere, C. et al. Asprosin, a fasting-induced glucogenic protein hormone. Cell 165, 566–579 (2016).

    CAS  Article  Google Scholar 

  2. 2

    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).

    Article  Google Scholar 

  3. 3

    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).

    Article  Google Scholar 

  4. 4

    Judge, D.P. & Dietz, H.C. Marfan's syndrome. Lancet 366, 1965–1976 (2005).

    CAS  Article  Google Scholar 

  5. 5

    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).

    CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    Krashes, M.J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Denis, R.G.P. et al. Palatability can drive feeding independent of AgRP neurons. Cell Metab. 22, 646–657 (2015).

    CAS  Article  Google Scholar 

  11. 11

    Atasoy, D., Betley, J.N., Su, H.H. & Sternson, S.M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).

    CAS  Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    Garfield, A.S. et al. A neural basis for melanocortin-4 receptor–regulated appetite. Nat. Neurosci. 18, 863–871 (2015).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Nakajima, K. et al. Gs-coupled GPCR signaling in AgRP neurons triggers sustained increase in food intake. Nat. Commun. 7, 10268 (2016).

    CAS  Article  Google Scholar 

  16. 16

    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).

    Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    Schoeller, D.A. Measurement of energy expenditure in free-living humans by using doubly labeled water. J. Nutr. 118, 1278–1289 (1988).

    CAS  Article  Google Scholar 

  20. 20

    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).

    CAS  Article  Google Scholar 

  21. 21

    National Research Council. Guide for the Care and Use of Laboratory Animals 8th edn. (The National Academies Press, 2011).

  22. 22

    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).

    CAS  Article  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Berglund, E.D. et al. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J. Clin. Invest. 123, 5061–5070 (2013).

    CAS  Article  Google Scholar 

  26. 26

    Cao, X. et al. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice. J. Clin. Invest. 124, 4351–4362 (2014).

    CAS  Article  Google Scholar 

  27. 27

    Xu, P. et al. Activation of serotonin 2C receptors in dopamine neurons inhibits binge-like eating in mice. Biol. Psychiatry 81, 737–747 (2017).

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    Ren, H. et al. FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149, 1314–1326 (2012).

    CAS  Article  Google Scholar 

  30. 30

    Sohn, J.-W. et al. Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. Cell 152, 612–619 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Liu, Y. et al. Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat. Protoc. 8, 1670–1679 (2013).

    CAS  Article  Google Scholar 

  32. 32

    Liu, T. et al. Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73, 511–522 (2012).

    Article  Google Scholar 

  33. 33

    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).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Contributions

A.R.C. and Y.X. conceptualized the study; C.D., Y.H., C.W., C.L., J.C.B., C.R., P.K.S., M.J.K., and A.R.C. performed experiments; V.R.S., N.F.B., and A.R.C. performed clinical assessment of individuals with NPS; M.E.L., K.J.P., M.J., M.F., Q.W., D.M.M., and D.D.M. provided resources; P.J. and Z.Z. performed the ANCOVA analysis; and A.R.C. wrote the manuscript.

Corresponding authors

Correspondence to Yong Xu or Atul R Chopra.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1–9 and Supplementary Tables 1–2 (PDF 1887 kb)

Life Sciences Reporting Summary (PDF 159 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing