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Published on: May 24, 2018
Disruption of Ephb1 causes reduced hypothalamic CRH and TRH expression and obesity in mice
Simin Xie1, Tao Zhao1, Chengchen Hu1
1State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
Objective:
Ephrin type-B receptor 1 (EphB1) is a receptor tyrosine kinase involved in axon guidance, synaptic plasticity, and tumorigenesis. However, the role of EphB1 in metabolic regulation and obesity remains poorly understood. This study aims to uncover the role of EphB1 in energy metabolism and provide insights into the underlying mechanisms by which EphB1 regulates obesity.
Methods:
Two Ephb1 mutations identified from a forward genetic screen for obesity-related loci in mice were examined for their effects in gene expression, energy metabolism, and endocrine changes. The impacts of EphB1 on neuropeptide expression and signal transduction were evaluated in both hypothalamic tissues and primary cells. Potential downstream signals were modified in Ephb1 mutants to verify the interaction.
Results:
Ephb1 mutants develop obesity in adolescence and develop impaired glucose tolerance during adulthood. EphB1 deficiency caused lower body temperature, blunted cold-induced thermogenesis, and decreased locomotor activity, but it did not alter food intake. EphB1 promotes cyclic AMP-responsive element-binding protein (CREB) phosphorylation via phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling in a cell-autonomous manner. EphB1 deficiency leads to reduced expression of corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) in the brain. Intraventricular administration of either TRH or a CRH fragment suppressed obesity in Ephb1 mutants.
Conclusions:
EphB1 regulates hypothalamic CRH and TRH expression and promotes energy expenditure in mice.
Insights
Ephrin type-B receptor 1 (EphB1) deficiency causes obesity in mice by impairing energy expenditure and hypothalamic neuropeptide expression. Restoring these neuropeptides ameliorates obesity, highlighting EphB1's role in metabolic regulation.
Area of Science:
- Neuroscience
- Metabolic Regulation
- Receptor Tyrosine Kinases
Background:
- Ephrin type-B receptor 1 (EphB1) is a receptor tyrosine kinase implicated in axon guidance, synaptic plasticity, and tumorigenesis.
- The role of EphB1 in metabolic regulation and obesity is not well understood.
Purpose of the Study:
- To investigate the role of EphB1 in energy metabolism and its mechanisms in regulating obesity.
- To uncover the underlying molecular pathways through which EphB1 influences metabolic processes.
Main Methods:
- Examined Ephb1 mutations in mice for effects on gene expression, energy metabolism, and endocrine changes.
- Evaluated EphB1's impact on neuropeptide expression and signaling in hypothalamic tissues and primary cells.
- Modified downstream signals in Ephb1 mutants to confirm interactions.
Main Results:
- Ephb1 mutants exhibited obesity and impaired glucose tolerance, with reduced body temperature, blunted thermogenesis, and decreased activity, independent of food intake.
- EphB1 signaling, via PI3K/AKT, promotes CREB phosphorylation in a cell-autonomous manner.
- EphB1 deficiency reduced hypothalamic CRH and TRH expression, and TRH or CRH administration suppressed obesity in mutants.
Conclusions:
- EphB1 plays a crucial role in regulating hypothalamic CRH and TRH expression.
- EphB1 promotes energy expenditure and is a key regulator of energy balance and obesity in mice.
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