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 (LepRb Glp1r ) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRb Glp1r 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 LepRb Glp1r neurons in otherwise Glp1r -null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRb Glp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.

Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents

“…Rupp et al demonstrated that neurons in the dorsomedial hypothalamus (DMH) exhibit sensitivity to both leptin and liraglutide 43 . They further found that the reactivation of glp1r , specifically in neurons expressing the leptin receptor, was adequate for liraglutide to effectively suppress food intake.…”

Efficacy and Safety of Glucagon-Like Peptide 1 Agonists in a Retrospective Study of Patients With Familial Partial Lipodystrophy

“…Therefore, it is foreseeable that the effect of GLP-1RA improves first-phase insulin secretion and offsets zthe high DPP-4 levels, which lead to reduced glucose level, reduced weight, a lower body adiposity index, and an improved lipid profile ( 14 ). Finally, the possibility of GLP-1 to work as a leptin sensitizer centrally may be an important contributor ( 15 , 16 ).…”

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

“…To investigate neurons that co-express Lepr , Glp1r, and Slc32a1, such as the Trh Arc neurons described here, a recent study used conditional knock-out and rescue strategies to better define the role of these neurons in body weight maintenance 4 . The authors found that deleting Lepr expression from Glp1r + cells stimulated weight gain through overeating.…”

“…However, no such rescue occurred if GABAergic Glp1r + neurons were excluded from the Lepr reactivation, indicating that leptin acts on GABAergic Glp1r + neurons to control feeding and body weight. Importantly, a similar knockout and conditional reactivation approach showed that expressing Glp1r only in GABAergic Lepr + cells was sufficient for liraglutide to suppress appetite 4 . The study concluded that the likely site of interaction of liraglutide and leptin was the DMH given the abundance of leptin-sensing Glp1r + neurons there 4 .…”