Hypothalamic signaling mechanisms linking angiotensin and melanocortin pathways for metabolic control

摘要/摘要 肥胖是发展高血压和其他心血管疾病的主要危险因素， 并且目前预防和逆转肥胖症的治疗方法是不够的。美国国立卫生研究院的研究， 其他人已经证明，人类肥胖和对体重减轻的抵抗与抑制 静息时的能量消耗（称为静息代谢率或RMR）。虽然临床研究利用一系列 药品（2，4-二硝基苯酚等）提供了概念验证数据，强调RMR的效用 刺激逆转肥胖，所有现有的刺激RMR的药物都表现出不安全的药代动力学 因此被禁止用于人类。制定下一代治疗战略， 肥胖症的流行需要增加对RMR的生物控制器的理解。下丘脑， 更具体地说，弓状核（ARC）在RMR的综合控制中起关键作用，我们 最近已经证明了血管紧张素II 1A型（AT 1A）受体的作用，定位于刺豚鼠相关的 ARC的肽（AgRP）神经元，在RMR的控制中由多种刺激物，包括瘦素， 高脂饮食和脑肾素-血管紧张素系统（RAS）。本提案的目的是 了解由AT 1A激活的AgRP神经元内的第二信使信号级联， 阐明ARC RAS介导RMR控制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，AT 1A的AgRP神经元，而独特地激活G- α-i-2（GNAI 2）级联，其对通过G蛋白信号传导-2（RGS 2）的调节剂的调节敏感。 此外，我们假设该级联介导了AgRP神经传递的控制，因此， 通过其4型受体（MC 4 R）激活黑皮质素介导的信号传导。最后，新数据支持了 RGS 2还调节MC 4 R第二信使信号传导，并且其本身受MC 4 R调节的新概念 信号传导，导致MC 4 R神经元内的自动调节级联反应，这可能是心脏代谢的基础。 在目前的方案中，各项目都探讨了提高认识的问题。

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 Based on exciting new unpublished data, we hypothesize that AT1A on AgRP neurons rather uniquely activates a G- alpha-i-2 (GNAI2) cascade, which is sensitive to modulation by regulator of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.