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Melanocortin signaling in the CNS directly regulates circulating cholesterol

Nature Neuroscience volume 13, pages 877–882 (2010)Cite this article

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Abstract

Cholesterol circulates in the blood in association with triglycerides and other lipids, and elevated blood low-density lipoprotein cholesterol carries a risk for metabolic and cardiovascular disorders, whereas high-density lipoprotein (HDL) cholesterol in the blood is thought to be beneficial. Circulating cholesterol is the balance among dietary cholesterol absorption, hepatic synthesis and secretion, and the metabolism of lipoproteins by various tissues. We found that the CNS is also an important regulator of cholesterol in rodents. Inhibiting the brain's melanocortin system by pharmacological, genetic or endocrine mechanisms increased circulating HDL cholesterol by reducing its uptake by the liver independent of food intake or body weight. Our data suggest that a neural circuit in the brain is directly involved in the control of cholesterol metabolism by the liver.

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Figure 1: Ghrelin and melanocortin action in the CNS control of plasma HDL-C.
Figure 2: Altered plasma cholesterol in mutant mice deficient for ghrelin or melanocortin signaling.
Figure 3: Gut hormones and melanocortin action in the CNS modulates hepatic HDL-C re-uptake pathways independent of food intake.
Figure 4: Effect of the gut hormone ghrelin and melanocortin action in the CNS on the hepatic gene expression of components of cholesterol synthesis pathway.
Figure 5: Animal models with increased susceptibility to diet-induced obesity and decreased hypothalamic melanocortin signaling have increased HDL-C.

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Acknowledgements

This work was supported by US National Institute of Health grants NIDDK56863 (S.C.W. and M.H.T.), 5R01DK077975 (M.H.T.), R01 DK076907 (D.Y.H.) and HL67093 (W.S.D.). S.M.H. is the recipient of a Scientist Development Award from the American Heart Association (#0635079N). S.M.H. is a recipient of a Basic Science Award (1-10-BS-72) from the American Diabetes Association.

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Author notes

  1. James L Trevaskis & Andrew A Butler

    Present address: Present addresses: Amylin Pharmaceuticals, San Diego, California, USA (J.L.T.), Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida, USA (A.A.B.).,

Authors and Affiliations

  1. Division of Endocrinology, Departments of Medicine and Psychiatry, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Diego Perez-Tilve, Susanna M Hofmann, Ruben Nogueiras, Paul T Pfluger, Erin Grant, Hilary E Wilson-Perez, Stephen C Woods, Stephen C Benoit & Matthias H Tschöp

  2. Department of Pathology, Lipid Research Centre & Metabolic Disease Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Joshua Basford, Norman A Granholm, William S Davidson & David Y Hui

  3. Department of Chemistry, Indiana University at Bloomington, Bloomington, Indiana, USA

    James T Patterson & Richard D DiMarchi

  4. Institute of Animal Science, ETH-Zurich, Schwerzenbach, Switzerland

    Myrtha Arnold

  5. Neuropeptides Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA

    James L Trevaskis & Andrew A Butler

  6. Regeneron Pharmaceuticals, Tarrytown, New York, USA

    Mark W Sleeman

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Contributions

D.P.-T., S.M.H., J.B., R.N. and P.T.P. designed and performed most of the experiments and wrote the manuscript. J.L.T. performed experiments, J.T.P. synthesized receptor ligands and A.A.B., S.C.B. and M.W.S. generated mouse models. N.G. carried out FPLC analyses. W.S.D. performed lipoprotein electrophoresis, E.G. and H.W.-P. carried out in vivo experiments, gene expression, inmunoblots and inmunoassays, M.A. performed surgical procedures and S.C.W. interpreted data and co-wrote the manuscript. R.D.D., D.Y.H. and M.H.T. conceptualized, analyzed and interpreted all studies and co-wrote the manuscript.

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Correspondence to Matthias H Tschöp.

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Competing interests

R.D.D. and M.H.T. are scientific advisors for and shareholders of Marcadia Biotech and Ambrx Inc.

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Perez-Tilve, D., Hofmann, S., Basford, J. et al. Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nat Neurosci 13, 877–882 (2010). https://doi.org/10.1038/nn.2569

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