Mechanisms of action for dorsomedial hypothalamic Lepr-Glp1r neurons that control feeding and energy balance
控制摄食和能量平衡的下丘脑背内侧 Lepr-Glp1r 神经元的作用机制
基本信息
- 批准号:10748011
- 负责人:
- 金额:$ 4.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAdultAppetite StimulantsBody WeightBrainBrain StemCardiovascular DiseasesCell NucleusCellsCentral Nervous SystemDataDesire for foodDetectionDiabetes MellitusEatingExhibitsFastingFeedbackFeeding behaviorsFood EnergyGLP-I receptorGene Expression RegulationGlutamatesHealthHealthcareHeart DiseasesHomeostasisHypothalamic structureIncidenceInstitutionLaboratoriesLeptinModelingMusNeuronsNon-Insulin-Dependent Diabetes MellitusObesityOutcomePeptidesPlayPopulationPopulation ControlPrevalencePro-OpiomelanocortinReceptor SignalingRegulationRoleSatiationSignal TransductionSiteStructure of dorsomedial hypothalamic nucleusStructure of nucleus infundibularis hypothalamiSystemTestingTetanus ToxinTherapeutic InterventionWeight GainWorkcombatdesigndiet-induced obesityenergy balancefeedinghindbrainhormonal signalsimprovedin vivoinhibitorleptin receptormolecular markernew therapeutic targetnovelnovel therapeuticsobese patientsobesity treatmentreceptor expressionresponserestraintsingle nucleus RNA-sequencing
项目摘要
ABSTRACT
Obesity promotes type 2 diabetes and other adverse health outcomes, placing a significant burden on our
healthcare institutions- as well as patients with obesity. The brain contains systems that modulate feeding and
body weight over the long term. Many of these systems reside in the hypothalamus, which controls food intake
and energy homeostasis in response to a host of signals, including leptin (a hormonal signal of body energy
stores) and feeding-activated neurons in the brainstem nucleus tractus solitarius (NTS). To design new therapies
to combat obesity we must understand the brain systems that control feeding and body weight, including the
hypothalamic circuits that integrate input from leptin and the hindbrain.
Prior work demonstrated that GABAergic Lepr neurons that reside in the dorsomedial hypothalamus (DMH)
make important contributions to the control of feeding behavior, including in the suppression of orexigenic
arcuate nucleus (ARC) AgRP neurons by leptin and feeding. Additionally, our recent results showed that several
populations of food intake-suppressing glutamatergic NTS neurons project to the DMH and inhibit AgRP
neurons. While these finding suggest that a population of GABAergic DMH LepRb neurons integrates signals
from leptin and the NTS to suppress food intake by inhibiting AgRP neurons, the DMH contains many populations
of neurons with different functions, including multiple groups of GABAergic LepRb neurons. Our laboratory used
single nucleus RNA sequencing to identify known and novel populations of LepRb neurons, including a novel
population of GABAergic DMH LepRb neurons marked by glucagon-like peptide 1 (GLP-1) receptor (Glp1r)
expression (LepRbGlp1r neurons). We found that LepRbGlp1r neurons play essential roles in the control of food
intake by leptin. We hypothesize that these LepRbGlp1r neurons represent the crucial population of GABAergic
DMH LepRb neurons that integrate signals from leptin and the NTS to suppress food intake by inhibiting AGRP
neurons. To test this overall hypothesis, we will test the notions that: (1) DMH LepRbGlp1r neurons receive direct
excitatory input from glutamatergic NTS neurons; (2) LepRbGlp1r neurons inhibit AgRP neurons and suppress
food intake; and (3) silencing LepRbGlp1r neurons will increase the activity of AgRP neurons and promote feeding
and weight gain.
摘要
项目成果
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