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 5

Requirement for Lepr in GABAergic Glp1r cells for the control of energy balance.

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Requirement for Lepr in GABAergic Glp1r cells for the control of energy ...
(A) Generation of LeprFSF-fl/FSF-fl (KO), Scl32a1FlpO;LeprLSL-fl/LSL-fl (ReVgat), and Scl32a1FlpO;Glp1rCre;LeprLSL-fl/LSL-fl (ReVgatKOGlp1r) mice to test the role of Lepr in GABAergic Glp1r neurons for leptin action. Because of the low number of animals produced by the breeding scheme, data from male and female animals has been combined. (B–H) Body weight (B; n = 2 ReVgat, n = 6 ReVgatKOGlp1r, and n = 13 KO male and n = 5 ReVgat, n = 10 ReVgatKOGlp1r, n = 9 KO female animals), food intake (C; n = 2 ReV, n = 3 ReVKOG, n = 8 KO male and n = 3 ReV, n = 7 ReVKOG, n = 8 KO female animals), body composition (D; n = 1 ReV, n = 2 ReVKOG, n = 8 KO male and n = 3 ReV, n = 6 ReVKOG, n = 4 KO female animals), serum leptin and serum insulin (E and F; n = 2 ReV, n = 2 ReVKOG, n = 4 KO male and n = 3 ReV, n = 7 ReVKOG, n = 3 KO female animals), blood glucose (G; n = 2 ReV, n = 6 ReVKOG, n = 13 KO male and n = 5 ReV, n = 10 ReVKOG, n = 9 KO female animals), and glycemic response to i.p. glucose tolerance test (H) in RevGAT (gold; n = 1 male and n = 5 female), KO (orange; n = 8 male and n = 5 female), and RevGATKOGlp1r (green; n = 2 male and n = 6 female) mice. In F and G, all mice were ad libitum fed in the AM. Data in B and H show the mean ± SEM; different letters signify conditions that are statistically different (P < 0.05) by ANOVA with Tukey’s post hoc test. For C–H, *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by ANOVA with Dunnett’s post hoc test.