Leptin Receptor Reactivation Restores Brain Function in Early-Life lepr-Deficient Mice
Reactivation of Insulin Receptors Can Restore Brain Function in Early Lepr-Deficient Mice
Background
Obesity is a chronic disease caused by excessive fat accumulation, affecting both body and brain health. Deficiency of the insulin receptor (Leptin receptor, Lepr) is considered an important factor in the pathogenesis of obesity. Insulin plays a crucial role in multiple neural processes and key developmental stages. Previous studies have shown that insulin deficiency during childhood leads to permanent developmental problems in young mice, such as energy homeostasis imbalance, changes in the melanocortin system and reproductive system, and reduced brain mass. In human studies, obesity is associated with brain atrophy and cognitive impairment, making it necessary to determine the long-term effects of childhood insulin deficiency on brain structure and memory function.
Research Source
This paper was written by Caroline Fernandes and a group of researchers, mainly from the Federal University of Rio de Janeiro, Queen’s University, and the University of São Paulo. The paper was published in the journal “Brain” on April 23, 2024. This study aimed to explore the effects of insulin deficiency on mouse brain development and memory, and to verify whether restoring insulin signaling could reverse these effects.
Research Process
The paper first studied Lepr-deficient mice (lepob). These mice exhibited changes in brain volume, decreased neurogenesis, and memory impairment. To understand the long-term effects of Lepr signal loss on the brain, researchers designed a series of experiments, including mouse sample acquisition and processing, brain imaging analysis, behavioral testing, and immunohistochemical analysis of cell neurogenesis.
Research Subjects and Sample Processing
The research subjects mainly included two types of mice: Lepr-deficient mice (lepob) and mice that do not express Lepr (leprnull). To explore the effects of restoring Lepr expression, researchers restarted Lepr expression in 10-week-old mice. All mice were provided by the University of São Paulo and housed in the laboratory of the Federal University of Rio de Janeiro in Rio de Janeiro.
Lepr Reactivation
The research team reactivated Lepr in 10-week-old mice by injecting tamoxifen (0.15mg/g). The injection schedule was completed within five days, with one injection per day.
Brain Imaging Analysis
7.0T magnetic resonance imaging (MRI) was used for brain imaging to observe and quantify brain and ventricular volumes. The study used two different imaging protocols, one without contrast agent and another using mn2+ as a contrast agent to enhance image contrast and clarity.
Behavioral Testing
In behavioral testing, the Morris Water Maze (MWM) was used to assess spatial learning and memory abilities in mice. The test found that lepob mice showed significant decreases in speed and travel distance, indicating impaired learning and memory abilities.
Cell Proliferation and Neurogenesis Assessment
The study assessed cell proliferation and neurogenesis through immunohistochemistry analysis, using Doublecortin (DCX) to mark newborn neuronal progenitor cells in the hippocampal dentate gyrus of mice.
Experimental Results
Brain Volume and Structure
MRI three-dimensional brain volume analysis showed that lepob mice had significantly reduced brain volume, indicating that insulin deficiency led to brain atrophy. Mice with reactivated Lepr restored their brain weight to levels similar to wt mice, suggesting that long-term adult Lepr reactivation reversed the brain atrophy phenotype caused by lack of Lepr signaling.
Behavioral and Memory Performance
MWM test results showed that both lepob and leprnull mice exhibited learning and memory deficits, while mice with reactivated Lepr showed significant improvement. This indicates that loss of Lepr signaling affects spatial learning and memory in mice, and restoring Lepr signaling in adulthood can reverse this impairment.
Neurogenesis
Cell proliferation and neurogenesis assessment results showed that lepob and leprnull mice had significantly reduced neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus. Mice with reactivated Lepr restored neurogenesis levels in these regions, demonstrating the importance of Lepr signaling in maintaining neurogenesis.
Conclusion
This study demonstrates the significant impact of insulin signaling deficiency during development on the brain, particularly on hippocampal neurogenesis and structure. By reactivating Lepr, it is possible to reverse brain atrophy and memory function impairment caused by early loss of insulin signaling. This suggests that insulin-based therapies may have potential applications in preventing or treating long-term cognitive impairments associated with obesity.
Research Highlights
- Important Findings: For the first time, systematically elucidated the long-term effects of Lepr deficiency in early life on adult mouse brain structure and function, and experimentally verified that restoring Lepr signaling can significantly improve this damage.
- Research Value: The study provides scientific evidence for future exploration of insulin-based therapeutic approaches to prevent and treat obesity-related neurodegenerative diseases.
- Methodological Innovation: The use of tamoxifen injection technique effectively reactivated Lepr in mice, combined with magnetic resonance imaging technology to accurately quantify brain volume changes, demonstrating high experimental scientific rigor and innovation.
Future Research Directions
Future research could focus on exploring how to optimize the restoration of Lepr signaling and its effects on other neurological diseases. Additionally, exploration of the insulin-like pathway will provide more clues to reveal the potential mechanisms of insulin in brain development.
Overall, the findings of this paper reveal the key role of insulin signaling in brain development and demonstrate the feasibility of restoring insulin signaling to reverse brain damage caused by early insulin deficiency, providing new ideas and directions for related treatments.