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

Sep 19, 2017Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

How Glucagon-Like Peptide-1 Signals in a Brain Area Controlling Motivation Help Regulate Energy Balance

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Abstract

Direct activation of LDTg GLP-1 receptors suppresses food intake by reducing average meal size.

GLP-1-producing neurons in the nucleus tractus solitarius project to the lateral dorsal tegmental nucleus (LDTg), indicating a neural pathway for GLP-1 signaling.
Pharmacological blockade of LDTg GLP-1 receptors increases food intake and diminishes the effects of gastric distension, suggesting a role in appetite regulation.
Systemically administered GLP-1 receptor agonists can access the LDTg, where they are positioned near neurons.
Blockade of LDTg GLP-1 receptors reduces the appetite-suppressing effects of systemic GLP-1 receptor agonists, highlighting the LDTg's involvement in energy balance.

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

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