Original Article

Neuropsychopharmacology accepted article preview 18 September 2017; doi: 10.1038/npp.2017.225

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Glucagon-like peptide-1 receptor signaling in the lateral dorsal tegmental nucleus regulates energy balance

David J Reiner1, Rosa M Leon1, Lauren E McGrath1, Kieran Koch-Laskowski1, Joel D Hahn2, Scott E Kanoski3, Elizabeth G Mietlicki-Baase1 and Matthew R Hayes1

  1. 1Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine and Department of Biological Sciences
  2. 2Neurobiology Section
  3. 3Human and Evolutionary Biology Section, University of Southern California

Correspondence: Dr MR Hayes:, Department of Psychiatry, University of Pennsylvania, Center for Neurobiology and Behavior, 125 S. 31st St, Philadelphia, PA 19104, USA, Tel: +215 573 6070, Fax: +215 573 2041, E-mail: hayesmr@mail.med.upenn.edu

Received 3 July 2017; Revised 12 September 2017; Accepted 13 September 2017
Accepted article preview online 18 September 2017



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 soliartius (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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