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CNS Fatty Acid Metabolism in Regulation of Food Intake

中枢神经系统脂肪酸代谢在食物摄入调节中的作用

基本信息

批准号：
7211429
负责人：
SUSAN M AJA
金额：
$ 13.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7211429
关键词：
5&apos -AMP-activated protein kinase Acute Address Adult Affect Appetitive Behavior Bathing Behavioral Biochemical Biological Assay Brain Carnitine O-Palmitoyltransferase Detection Eating End Point FOS gene Fatty-acid synthase Feeding behaviors Food Intake Regulation Frequencies Gene Expression Health High Pressure Liquid Chromatography Human Hypothalamic structure Immunohistochemistry In Situ Hybridization Individual Injection of therapeutic agent Learning Measures Mentored Research Scientist Development Award Mentors Messenger RNA Mus Neurons Neuropeptides Obesity Output Pattern Peptides Positioning Attribute Production Range Rattus Regulation Research Rodent Role Satiation Signal Transduction Solid Structure of nucleus infundibularis hypothalami Testing Training Universities experience fatty acid metabolism feeding in vivo mRNA Expression male medical schools neurophysiology novel oxidation research study response size

项目摘要

DESCRIPTION (provided by applicant): The objective of the proposal is to identify behavioral and cellular mechanisms by which inhibition of fatty acid synthase (FASi) and enhanced beta-oxidation by stimulation of carnitine-palmitoyltransferase-1 (CPT-1s) alter hypothalamic energy status and adjust food intake. The candidate will (1) gain experience with primary hypothalamic neuronal cultures and acute hypothalamic explants in static incubation, (2) learn a range of biochemical assays, and (3) build upon experience with HPLC, immunohistochemistry, and mRNA detection. The training will facilitate the candidate's transition to independent research. Experiments will be conducted at the Johns Hopkins University School of Medicine. The primary mentor is Dr. Gabriele Ronnett, a neuroscientist and biochemist who uses neuronal cultures. The co-mentor is Dr. Timothy Moran, an expert in neurophysiology of feeding. The candidate will interact with an interdisciplinary team that investigates roles of fatty acid metabolism in a range of human health problems, including obesity. C75 is a FASi/CPT-1s that reduces food intake and alters gene expression for hypothalamic feeding-related neuropeptides when given centrally to rodents. We find that icv C75 decreases feeding in rats by reducing meal frequency, not size, suggesting that FASi or CPT-1s, or both, reduce drive to initiate feeding, rather than enhance satiety. C75 affects energy status in primary cultures of hypothalamic neurons, altering intracellular signaling to modulate neuropeptide production. Novel compounds selective for potent FASi or CPT-1s are available to us to investigate individual roles of FAS and CPT-1 in feeding regulation. The overall hypothesis is that altered fatty acid metabolism in hypothalamic neurons changes their energy state and leads to homeostatic alterations in food intake. Experiments will address two Specific Aims: (1) Identify how FASi or CPT-1s in the brain alter food intake and gene expression: Experiments in mice will measure food intake, meal patterns, brain c-Fos expression, and expression of mRNA for feeding-related neuropeptides after icv C75, FASi, or CPT-1s. The second aim is to (2) Identify how FASi and CPT-1s change hypothalamic neuronal energy status and production of feeding-regulating neuropeptides: The compounds will be applied to (a) primary hypothalamic neuronal cultures and (b) acute hypothalamic explants. We will measure changes in intracellular AMP/ATP ratio and activity of AMP-activated protein kinase, levels of mRNAs for feeding-related neuropeptides, and neuropeptide production and release.

描述（由申请人提供）：