Resolving the effects of dietary fat induced maternal CXCL12 on offspring hypothalamus using spatial gene transcriptomics

利用空间基因转录组学解析膳食脂肪诱导的母体 CXCL12 对后代下丘脑的影响

• 批准号: 10509951
• 负责人: KINNING POON
• 金额: $ 7.99万
• 依托单位: COLLEGE AT OLD WESTBURY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10509951
• 关键词: Acute; Affect; Appetite Stimulants; Architecture; Bar Codes; Behavioral; Body Weight Changes; Brain; CXCL12 gene; CXCR4 gene; Characteristics; Chronic; Cohort Effect; Complementary DNA; Complex; Detection; Development; Diet; Dietary Fats; Eating; Embryo; Embryonic Development; Energy Intake; Enkephalins; Environment; Event; Exposure to; Fatty acid glycerol esters; Feeding behaviors; Female; Gene Expression; Genes; Goals; High Fat Diet; Histology; Hyperphagia; Hypothalamic structure; Immunofluorescence Immunologic; Inflammation; Inflammation Mediators; Inflammatory; Ingestion; Intake; Label; Location; Measures; Messenger RNA; Modeling; Modification; Motor Activity; Neuroglia; Neurologic; Neurons; Neuropeptides; Obesity; Outcome; Peptides; Physiological; Play; Pregnancy; Process; Proteins; Rattus; Research; Resolution; Risk; Role; Techniques; Testing; anxiety-like behavior; base; behavior change; behavior test; cell type; chemokine; cytokine; dietary excess; in utero; insight; inter-alpha-inhibitor; male; neurogenesis; neuron development; neutralizing antibody; novel; offspring; paraventricular nucleus; prenatal; prevent; receptor; sex; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Excessive intake of a diet rich in fats during pregnancy gives rise to offspring that are prone to overeating dietary fat and becoming obese. This generational effect of prenatal programming of ingestive behavior results in offspring that are prone to becoming obese. This proneness in offspring is attributed to an increase in the genesis of orexigenic enkephalin neurons in the hypothalamus. High levels and expression of hypothalamic enkephalin is a stimulator of high-fat diet intake. One potential mechanism for this change involves the chemokine CXCL12, which has been shown to be altered by the intake of a high-fat diet. Maternal CXCL12, similar to a high-fat diet, can also stimulate enkephalin levels and ingestive behavior in offspring. Currently, it is unknown how prenatal high-fat diet exerts its affects through CXCL12 to change the hypothalamic architecture in developing embryos. The goal of this proposal in using a rat model is pilot whether the reduction of maternal CXCL12 levels could prevent offspring brain changes. Aim 1a will examine the effects of CXCL12-neutralizing antibody paired with maternal HFD ingestion on changes in offspring hypothalamus. Utilizing the novel spatial gene transcriptome technique, immunofluorescence histology labeling of neurons and neuroglia in conjunction with markers of genesis and orexigenic neuropeptides will be performed. Afterwards, discrete regions of the hypothalamus will be barcoded, and the mRNA (resulting cDNA) will be collected for RNAseq. The results will provide unique location-based transcriptome changes overlaid by fluorescently labeled cell types. Aim 1b will test these same offspring for behavioral and weight changes that align with obesity-prone rats. Daily caloric intake and weight change will be tracked and behavioral tests to measure anxiety-like behavior, a marker for hyperphagia, will also be examined. These results will further support the hypothesis that HFD-induced increase in maternal CXCL12 plays a role in producing hyperphagic offspring and provide new higher resolution insight into neurogenesis events in offspring brain.

项目总结