Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models
Alan C. Rupp, … , Paul Kievit, Martin G. Myers Jr.
Alan C. Rupp, … , Paul Kievit, Martin G. Myers Jr.
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(19):e157515. https://doi.org/10.1172/JCI157515.
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Research Article Endocrinology Metabolism

Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models

Abstract

The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A potentially unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-Seq of enriched mouse hypothalamic LepRb cells, identifying several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations displayed strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRbGlp1r cells provoked hyperphagic obesity without impairing energy expenditure. Similarly, improvements in energy balance caused by Lepr reactivation in GABA neurons of otherwise Lepr-null mice required Lepr expression in GABAergic Glp1r-expressing neurons. Furthermore, restoration of Glp1r expression in LepRbGlp1r neurons in otherwise Glp1r-null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.

Authors

Alan C. Rupp, Abigail J. Tomlinson, Alison H. Affinati, Warren T. Yacawych, Allison M. Duensing, Cadence True, Sarah R. Lindsley, Melissa A. Kirigiti, Alexander MacKenzie, Joseph Polex-Wolf, Chien Li, Lotte Bjerre Knudsen, Randy J. Seeley, David P. Olson, Paul Kievit, Martin G. Myers Jr.

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Figure 2

Predominant DMH localization of LepRbGlp1r cells.

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Predominant DMH localization of LepRbGlp1r cells. (A) The number of Glp1...
(A) The number of Glp1r- (left), Npy- (middle), and Pomc-expressing (right) cells across LepRbSun1-sfGFP populations. (B) Representative image showing in situ hybridization for Gfp [LepRb(GFP), green] and Glp1r (magenta) in the hypothalamus of a LepRbEGFP-L10a mouse. Digital zooms of Glp1r (bottom), Gfp (middle), and merged images (top) are shown. Arrowheads indicate cells demonstrating colocalization. Original magnification, ×4. (C) Representative image showing GFP immunoreactivity (-IR) (green) and pSTAT3-IR [LepRb(pSTAT3), magenta] in the hypothalamus of a leptin-treated Glp1rEGFP-L10a mouse. Original magnification, ×4. A digital zoom of the boxed region is shown. (D) Quantification of cells containing GFP+pSTAT3 or GFP alone across hypothalamic nuclei in mice treated similarly as those shown in C (n = 3 male animals were assessed). (E) Representative images of the DMH showing FOS-IR (red) and Glp1r (GFP) in fasted (left; n = 3 male and 1 female animal) or fasted and refed with high-fat diet (right; n = 2 male and 2 female animals) Glp1rEGFP-L10a mice. Original magnification, ×4. Insets show digital zooms of the boxed regions. Quantification of FOS+GFP/GFP neurons is shown in the graph. Scale bar: 200 μm. ***P < 0.001 by Student’s t test.