Original Article

Glucagon-Like Peptide-1 Receptor Signaling in the Lateral Dorsal Tegmental Nucleus Regulates Energy Balance

  • Neuropsychopharmacology volume 43, pages 627637 (2018)
  • doi:10.1038/npp.2017.225
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Abstract

The neurobiological substrates that mediate the anorectic effects of both endogenous glucagon-like peptide-1 (GLP-1) and exogenous GLP-1 receptor (GLP-1R) agonists are an active area of investigation. As the lateral dorsal tegmental nucleus (LDTg) expresses the GLP-1R and represents a potential neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the major central source of GLP-1, with the other nuclei in the midbrain and forebrain, we tested the hypothesis that GLP-1R signaling in the LDTg controls food intake. Direct activation of LDTg GLP-1R suppresses food intake through a reduction in average meal size and independent of nausea/malaise. Immunohistochemical data show that GLP-1-producing neurons in the NTS project to the LDTg, providing anatomical evidence of endogenous central GLP-1 in the LDTg. Pharmacological blockade of LDTg GLP-1Rs with exendin-(9-39) dose-dependently increases food intake and attenuates the hypophagic effects of gastric distension. As GLP-1 mimetics are administered systemically in humans, we evaluated whether peripherally administered GLP-1R agonists access the LDTg to affect feeding. Immunohistochemical data show that a systemically administered fluorescent GLP-1R agonist accesses the LDTg and is juxtaposed with neurons. Additionally, blockade of LDTg GLP-1Rs attenuates the hypophagic effects of a systemic GLP-1R agonist. Together, these data indicate that LDTg GLP-1R signaling controls energy balance and underscores the role of the LDTg in integrating energy balance-relevant signals to modulate feeding.

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Acknowledgements

We thank Anh Cao, Jack Chen, Alexis Corini, Misgana Ghidewon, Joanna Krawczyk, Nina Juntereal, Rinzin Lhamo, Claudia Liberini, Tyler Ling, Celina Nhan, Chan Nguyen, Tram Pham, Lauren Stein, Evan Shaulson, and Christopher Turner for valuable technical assistance.

Author information

Author notes

    • Elizabeth G Mietlicki-Baase

    Current address: Department of Exercise and Nutrition Sciences, State University of New York at Buffalo, Buffalo, NY, USA

Affiliations

  1. Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Department of Biological Sciences, University of Pennsylvania, Center for Neurobiology and Behavior, Philadelphia, PA, USA

    • David J Reiner
    • , Rosa M Leon
    • , Lauren E McGrath
    • , Kieran Koch-Laskowski
    • , Elizabeth G Mietlicki-Baase
    •  & Matthew R Hayes
  2. Neurobiology Section, University of Southern California, Los Angeles, CA, USA

    • Joel D Hahn
  3. Human and Evolutionary Biology Section, University of Southern California, Los Angeles, CA, USA

    • Scott E Kanoski

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Corresponding author

Correspondence to Matthew R Hayes.

Supplementary information

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)