Hypothalamic signaling mechanisms linking angiotensin and melanocortin pathways for metabolic control

摘要/摘要 肥胖是高血压和其他心血管疾病发展的主要风险因素， 目前预防和逆转肥胖症的治疗方法是不够的。来自美国国立卫生研究院和 其他人已经证明，人类肥胖和对减肥的抵抗力，与抑制 静息能量消耗(称为静息代谢率，或RMR)。虽然临床研究利用了一系列 药品(2，4-二硝基苯酚等)提供了概念验证数据，强调了RMR的效用 刺激逆转肥胖，所有现有的刺激RMR的药物都显示出不安全的药代动力学 因此禁止人类使用。开发下一代治疗策略以对抗 肥胖的流行需要对RMR的生物控制者有更多的了解。下丘脑， 更具体地说，弓状核(ARC)在RMR的综合控制中起着关键作用，我们 最近证明了血管紧张素II1A型(AT1A)受体的作用，该受体定位于刺激物相关 ARC的多肽(AgRP)神经元，在RMR的控制下，由包括瘦素在内的各种刺激物控制， 高脂肪饮食和大脑肾素-血管紧张素系统(RAS)。目前提案的目标是 了解由AT1a激活的AgRP神经元内的第二信使信号级联，并 阐明ARC-RAS调节RMR的神经回路和神经递质。基于 令人兴奋的新的未发表的数据，我们假设在AgRP神经元上的AT1a相当独特地激活G- α-I-2(GNAI2)级联，对G蛋白信号转导调节因子-2(RGS2)的调节非常敏感。 此外，我们假设这一级联反应介导了AgRP神经传递的控制，因此 通过其类型4受体(MC4R)激活黑素皮质素介导的信号转导。最后，新的数据支持 RGS2还调制MC4R第二信使信号，并受MC4R自身调节 信号，导致MC4R神经元内的自我调节级联，这可能是心脏代谢的基础 在当前计划的项目中探索的敏感化。

Summary / Abstract Obesity represents a major risk factor for the development of hypertension and other cardiovascular disorders, and current therapeutic approaches to prevent and reverse obesity are insufficient. Studies from the NIH and others have demonstrated that human obesity, and resistance to weight loss, is related to the suppression of energy expenditure at rest (termed resting metabolic rate, or RMR). While clinical studies utilizing an array of pharmaceuticals (2,4-dinitrophenol, etc.) have provided proof-of-concept data highlighting the utility of RMR stimulation to reverse obesity, all existing pharmaceuticals that stimulate RMR exhibit unsafe pharmacokinetics and are therefore banned for human use. Development of next-generation therapeutic strategies to combat the obesity epidemic requires increased understanding of the biological controllers of RMR. The hypothalamus, and more specifically the arcuate nucleus (ARC), is critically involved in the integrative control of RMR, and we have recently documented a role for the angiotensin II type 1A (AT1A) receptor, localized to agouti-related peptide (AgRP) neurons of the ARC, in the control of RMR by a diverse array of stimulators including leptin, high fat diet, and the brain renin-angiotensin system (RAS). The objective of the current proposal is to understand the second-messenger signaling cascade within AgRP neurons which is activated by AT1A, and to clarify the neurocircuitry and neurotransmitters which mediate RMR control by the ARC RAS. Based on exciting new unpublished data, we hypothesize that AT1A on AgRP neurons rather uniquely activates a G- alpha-i-2 (GNAI2) cascade, which is sensitive to modulation by regulator of G-protein signaling-2 (RGS2). Further, we hypothesize that this cascade mediates control of AgRP neurotransmission and therefore the activation of melanocortin-mediated signaling through its type-4 receptor (MC4R). Finally, new data support the novel concept that RGS2 also modulates MC4R second-messenger signaling, and is itself regulated by MC4R signaling, which results in an autoregulatory cascade within MC4R neurons that may underlie cardiometabolic sensitization as explored across projects in the current program.