Article

A neural basis for melanocortin-4 receptor–regulated appetite

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Abstract

Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVHMC4R neurons and further identify these cells as a functional exponent of ARCAgRP neuron–driven hunger. Moreover, we reveal this function to be mediated by a PVHMC4R→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVHMC4R→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.

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Acknowledgements

The authors gratefully acknowledge the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Mouse Metabolism Core for technical support, V. Petkova and the Beth Israel Deaconess Medical Center Molecular Medicine Core Facility for assistance with quantitative PCR and sample preparation, and D. Morse for the production of the rabies virus. Sequencing and initial data processing were performed at Massachusetts General Hospital's Next-Gen Sequencing Core. Sequencing was supported in part by funding from the Boston Area Diabetes Endocrinology Research Center (BADERC P30 DK057521). This work was supported by the University of Edinburgh Chancellor's Fellowship (A.S.G.); US National Institutes of Health grants to B.B.L. (R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, BNORC Transgenic Core P30 DK046200, BADERC Transgenic Core P30 DK057521), to M.J.K. (F32 DK089710), to D.P.O. (K08 DK071561) and to J.K.E. (R01 DK088423 and R37 DK0053301); American Heart Association Postdoctoral Fellowship 14POST20100011 to J.N.C.; viral vector production core P30 NS045776 to B.A.T.; and an American Diabetes Association Mentor-Based Fellowship to B.P.S. and B.B.L. This research was supported, in part, by the Intramural Research Program of the NIH, NIDDK (DK075087, DK075088).

Author information

Author notes

    • Bhavik P Shah
    •  & David P Olson

    Present addresses: Cardiovascular and Metabolic Diseases, Pfizer, Cambridge, Massachusetts, USA (B.P.S.), and Division of Pediatric Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA (D.P.O.).

    • Alastair S Garfield
    • , Chia Li
    •  & Joseph C Madara

    These authors contributed equally to this work.

Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Alastair S Garfield
    • , Joseph C Madara
    • , Bhavik P Shah
    • , Jennifer S Steger
    • , John N Campbell
    • , David P Olson
    •  & Bradford B Lowell
  2. Centre for Integrative Physiology, Hugh Robson Building, University of Edinburgh, Edinburgh, UK.

    • Alastair S Garfield
  3. Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Chia Li
    • , Emily Webber
    •  & Michael J Krashes
  4. National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.

    • Chia Li
    • , Emily Webber
    •  & Michael J Krashes
  5. Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Oksana Gavrilova
  6. Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.

    • Charlotte E Lee
    •  & Joel K Elmquist
  7. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

    • Bakhos A Tannous
  8. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.

    • Bradford B Lowell

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Contributions

A.S.G., M.J.K., B.P.S. and B.B.L. conceived the studies. A.S.G., M.J.K., C.L. and J.C.M. conducted the studies with assistance from B.P.S., E.W., J.S.S. and D.P.O. Single cell RNA sequencing profiling was conducted by J.N.C. Energy expenditure assays were conducted by O.G. In situ validation of the MC4R-t2a-Cre mouse line was conducted by C.E.L. and J.K.E. Rabies virus was provided by B.A.T. A.S.G., M.J.K. and B.B.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alastair S Garfield or Michael J Krashes or Bradford B Lowell.

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