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Reducing the post weight-loss energy expenditure gap with orexin agonists

使用食欲素激动剂减少减肥后的能量消耗差距

基本信息

批准号：
10745184
负责人：
CATHERINE M KOTZ
金额：
$ 73.1万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2023-08-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745184
关键词：
Address Affinity Agonist Animal Model Animals Automobile Driving Behavioral Body Weight Body Weight decreased Brain Caloric Restriction Calories Chronic Compensation Consumption Data Drug Kinetics Eating Energy Metabolism Evaluation Excretory function Exercise Fatty acid glycerol esters Goals Homeostasis Human Hypothalamic structure Indirect Calorimetry Individual Injections Laboratories Left Metabolic Metabolism Mitochondria Modeling Molecular Mus Neurons Neuropeptides New Zealand Obese Mice Obesity Overweight Pattern Peptides Peripheral Physical Exercise Physical activity Play Property Public Health Rattus Regulation Relapse Reporting Respiration Rodent Model Role Sleep Structure Study models Subconscious System Testing Therapeutic Toxic effect Wakefulness Weight Weight Gain absorption abuse liability analog comorbidity design diet-induced obesity exercise program hypocretin improved improvement on sleep interest middle age neurochemistry obesity treatment orexin A prevent receptor research and development side effect small molecule therapy development total energy expenditure

项目摘要

Project Summary Following weight loss, the new lower body weight is extremely difficult to maintain. Many studies have now shown this is because individuals who lose a significant amount of body weight typically have an “Energy Expenditure Gap” (EEgap) post-weight loss, defined operationally as total energy expenditure (TEE) in the pre-obese state, minus TEE in the post-weight loss state, when at the same body weight. Recent studies suggest that the EEgap may be caused in part by compensatory and enduring reductions in basal energy expenditure (BEE) resulting from increases in activity-induced energy expenditure (AEE). Therefore, someone who has lost significant weight has to consume less and expend more energy to stay weight-stable compared to weight-matched individuals who have never been overweight. Physical activity ranges from a subconscious drive to move (spontaneous physical activity, SPA) to voluntary, structured, goal-oriented and high-intensity physical activity (programmed exercise). Increasing EE through physical activity, in combination with caloric restriction is a common therapeutic approach for weight loss, but most individuals do not adhere to physical exercise programs or maintain sufficient intensity to compensate for reductions in TEE post weight-loss. Our lab is one of few to study CNS regulation of SPA and have focused on the hypothalamic neuropeptide orexin A (OXA), which plays a central role in promoting wakefulness and energy homeostasis. We found that OXA injection and/or orexin neuron activation reverses BEE reductions and increases NEAT and TEE in animal models, without compensatory increases in food intake. Our collaborator Dr. Zhang is on the forefront of developing new small molecular orexin agonists that activate both orexin 1(OX1R) and orexin 2 (OX2R) receptors, and one such OX agonist upon i.p. administration robustly enhances SPA without changing food intake in middle aged mice and 5-mo old obesity prone (OP) rats. In addition, chronic (5wk) administration of the agonist reduced adiposity and weight gain in the New Zealand Obese (NZO) mice, supporting orexin agonists as a potential therapy to prevent weight relapse post weight-loss. The goal of the current project is to test the effects of these orexin agonists in reducing the EEgap, following weight-loss in rodent models of obesity, and to understand if the underlying mechanism involves alterations in mitochondrial respiration. We will also test the effect of these agonists on sleep/wake patterns for side effects. To do this, we will use indirect calorimetry in conjunction with behavioral analyses and peripheral administration of orexin agonist(s), to determine if activation of the orexin system suppresses weight regain. The long-term goal of this project is to enable research and development in using orexin as a therapy for obesity, weight regain and associated comorbidities.

项目总结