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Asprosin is a centrally acting orexigenic hormone

Nature Medicine volume 23, pages 1444–1453 (2017)Cite this article

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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.

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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.

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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.

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Author notes

  1. Clemens Duerrschmid, Yanlin He and Chunmei Wang: These authors contributed equally to this work.

  2. Yong Xu and Atul R Chopra: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

    Clemens Duerrschmid, Juan C Bournat, Chase Romere, Pradip K Saha, Mark E Lee, Kevin J Phillips, David D Moore, Yong Xu & Atul R Chopra

  2. Department of Pediatrics, USDA–ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA

    Yanlin He, Chunmei Wang, Monica Farias, Qi Wu, Nancy F Butte & Yong Xu

  3. Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA

    Chia Li & Michael J Krashes

  4. National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, Maryland, USA

    Chia Li & Michael J Krashes

  5. Kennedy Krieger Institute, Baltimore, Maryland, USA

    Mahim Jain

  6. Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Peilin Jia & Zhongming Zhao

  7. Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Dianna M Milewicz

  8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    V Reid Sutton & Atul R Chopra

Authors
  1. Clemens Duerrschmid
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  2. Yanlin He
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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.

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The authors declare no competing financial interests.

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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

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