Beta-ARs and Diet-Induced Thermogenesis

Beta-AR 和饮食诱导的生热作用

• 批准号: 7061329
• 负责人: BRADFORD B LOWELL
• 金额: $ 35.11万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-30 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061329
• 关键词: adipocytes; alpha adrenergic receptor; animal genetic material tag; beta adrenergic receptor; bioenergetics; brown fat; dietary excess; gene targeting; genetically modified animals; hormone receptor; hormone regulation /control mechanism; human genetic material tag; laboratory mouse; leptin; molecular cloning; nutrient interaction; nutrition related tag; obesity; photon absorptiometry; proopiomelanocortin; protein structure function; receptor expression; thermogenesis

DESCRIPTION (provided by applicant): Excessive caloric intake is sensed by the brain, which then activates thermogenesis as a means of preventing obesity. The sympathetic nervous system, through beta-adrenergic receptor (betaAR) action on target tissues, is likely the efferent arm of this homeostatic mechanism. To test this, mice lacking the three betaARs (beta-Iess mice) have been generated. Beta-less mice on a chow diet have reduced metabolic rate and are slightly obese. On a high-fat diet, beta-Iess mice develop massive obesity that is due entirely to failure of diet-induced thermogenesis. These findings establish that betaARs are necessary for diet-induced thermogenesis and that this pathway is critical in the defense against diet-induced obesity. Evidence supports the view that brown fat may be responsible for diet-induced thermogenesis, and that UCP1-driven uncoupled respiration is the intracellular mechanism. However, arguing strongly against this is the fact that UCP1 gene knockout mice, despite being cold sensitive, are lean and resist diet-induced obesity. The overall goal of this proposal is to identify the tissues and pathways which mediate diet-induced thermogenesis. Specific Aim #1: To establish which betaAR subtypes mediate diet-induced thermogenesis and protection from diet-induced obesity. Specific Aim #2: To identify the target tissue mediating diet-induced thermogenesis and protection from diet-induced obesity. Specific Aim #3" To establish a model of complete and specific brown adipose tissue deficiency in order to determine if brown fat plays a role in diet-induced thermogenesis and protection from diet-induced obesity. Specific Aim #4: To determine the role of betaAR signaling in mediating thermogenesis caused by central activation of leptin and melanocortin-4 (MC4) receptors.

描述（由申请人提供）：大脑感知过过多的热量摄入，然后激活热生成作为预防肥胖症的一种手段。通过β-肾上腺素能受体（BETAAR）对靶组织的作用，交感神经系统可能是这种体内稳态机制的传递臂。为了测试这一点，已经产生了缺乏三个β-iess小鼠的小鼠。食物饮食上的无β小鼠的代谢率降低，肥胖。在高脂饮食上，β-iess小鼠会发展出巨大的肥胖症，这完全是由于饮食引起的热生成的失败。这些发现表明，βARS对于饮食引起的热生成是必要的，并且该途径对于防御饮食引起的肥胖症至关重要。证据支持这样的观点，即棕色脂肪可能负责饮食引起的热发生，而UCP1驱动的未耦合呼吸是细胞内机制。然而，强烈反对这一点的事实是，尽管敏感性敏感，但UCP1基因敲除小鼠却是瘦弱的，并且可以抵抗饮食引起的肥胖症。该提案的总体目标是确定介导饮食引起的热发生的组织和途径。特定目的＃1：确定哪种βAR亚型介导饮食诱导的热发生并保护饮食引起的肥胖症。特定目的＃2：确定介导饮食引起的热生成并保护饮食引起的肥胖症的目标组织。具体目的＃3“建立一个完整和特定的棕色脂肪组织缺乏症的模型，以确定棕色脂肪是否在饮食诱导的热发生并保护饮食引起的肥胖症中起作用。具体目的＃4：确定βAR信号在介导的作用中，由leptin和Melanocortin-4（Mc4）受体的中枢激活引起的中枢热激活引起的介导热发生。