Department of Internal Medicine and.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
J Clin Invest. 2023 Oct 2;133(19):e157515. doi: 10.1172/JCI157515.
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.
脂肪组织来源的激素瘦素通过其在大脑中的受体（LepRb）发挥作用，以控制能量平衡。一群潜在未被识别的 GABA 能下丘脑 LepRb 神经元在瘦素抑制食物摄入和体重方面发挥着关键作用。为了以无偏倚的方式鉴定候选 LepRb 神经元群体的标志物，我们对富集的小鼠下丘脑 LepRb 细胞进行了单细胞 RNA-Seq，鉴定出了几个以前未被识别的下丘脑 LepRb 神经元群体。这些群体中的许多在物种间表现出很强的保守性，包括表达更多 Lepr 的 GABA 能 Glp1r 表达的 LepRb（LepRbGlp1r）神经元。从 LepRbGlp1r 细胞中敲除 Lepr 会引起暴食性肥胖，而不会损害能量消耗。同样，在其他 Lepr 缺失小鼠的 GABA 神经元中重新激活 Lepr 引起的能量平衡改善，需要 GABA 能 Glp1r 表达的 LepRb 神经元中的 Lepr 表达。此外，在其他 Glp1r 缺失小鼠中恢复 LepRbGlp1r 神经元中的 Glp1r 表达，使 GLP1R 激动剂利拉鲁肽能够抑制食物摄入。因此，保守的 GABA 能 LepRbGlp1r 神经元群体在瘦素和 GLP1R 激动剂抑制食物摄入方面发挥着关键作用。
