Effects of mesolimbic amylin signaling on macronutrient intake

项目摘要/摘要 肥胖症在美国非常普遍，但可用的治疗选择仍然有限。这个 多肽激素胰淀素可以减少食物摄入量和体重，被认为是一种很有前途的潜力。 目标是寻找新的肥胖治疗方法。由于肥胖在一定程度上是由高口感食品的过度消费推动的， 研究与摄食有关的信号，如胰淀素是如何在 大脑中与奖赏相关的核团控制食物摄入量。中脑边缘腹侧被盖区 奖赏系统在生理和药理学上都与胰淀素介导的食物抑制有关 摄入量，但VTA淀粉素促进负能量的行为和生理机制 平衡问题仍未得到解决。本提案旨在评估VTA淀粉素 信号会抑制特定膳食中大量营养素的摄入，从而促进能量负平衡。 研究还进一步调查了VTA胰淀素介导的摄食和身体控制的性别差异 体重，特别关注雌二醇对VTA胰淀素受体作用的影响 激活。特殊目的I将测试VTA胰淀素信号调节多巴胺信号的机制 以抑制特定膳食中大量营养素的摄入。首先，假设VTA胰淀素受体(AmyR) 激活有效地抑制伏隔核核心的时相性多巴胺，这是另一个关键的中脑边缘核 细胞核对口腔内脂肪的反应将用快速扫描循环伏安法进行评估。我们还将调查 嗅觉与消化后反馈对VTA AmyR表达激活的相对贡献 多巴胺神经元。此外，我们将使用依赖于Cre的腺相关病毒(AAV)来敲除AmyR 在VTA多巴胺神经元中的表达，并检测该神经元群体如何对内源性 胰淀素对能量平衡的控制。《特定目标2》通过评估来解决文献中的关键空白 VTA-AmyR在控制可口食物摄入量和体重中的生理和药理学意义 并将测试雌二醇对VTA AmyR信号的能量平衡效应的影响。我们 还将评估雌激素如何改变VTA中AmyR组分的表达，从而提供新的 雌激素和胰淀素在能量平衡控制中的中枢相互作用的机械性洞察。这些研究 在PI之前的K01和R03奖项的基础上，通过调查神经和行为机制 哪个中缘胰淀素信号促进负能量平衡，并将解决这一问题的新方面 通过提供对VTA胰淀素信号控制机制的更深层次的洞察力来研究领域 大量营养素的摄入量以及性别差异对这些影响。总的来说，这些研究将提供 关于胰淀素减少食物摄入量和促进减肥的作用机制的信息， 可能反过来促进开发更有效的治疗肥胖症的药物疗法。

Project Summary/Abstract Obesity is highly prevalent in the United States, yet available treatment options remain limited. The peptide hormone amylin, which reduces food intake and body weight, is thought to be a promising potential target for novel obesity treatments. As obesity is driven in part by overconsumption of highly palatable, rewarding foods, there is growing interest in examining how feeding-relevant signals such as amylin act at reward-relevant nuclei of the brain to control food intake. The ventral tegmental area (VTA) of the mesolimbic reward system is both physiologically and pharmacologically relevant for amylin-mediated suppression of food intake, but the behavioral and physiological mechanisms by which VTA amylin promotes negative energy balance remain unresolved. This proposal is designed to evaluate mechanisms by which VTA amylin signaling suppresses intake of particular dietary macronutrients to promote negative energy balance. Studies also further investigate sex differences in VTA amylin-mediated control of feeding and body weight, with particular focus on the influence of estradiol on the effects of VTA amylin receptor activation. Specific Aim I will test mechanisms by which VTA amylin signaling modulates dopamine signaling to suppress intake of particular dietary macronutrients. First, the hypothesis that VTA amylin receptor (AmyR) activation potently suppresses phasic dopamine in the nucleus accumbens core, another key mesolimbic nucleus, in response to intraoral fat will be evaluated with fast-scan cyclic voltammetry. We will also investigate the relative contribution of orosensory versus postingestive feedback to activation of VTA AmyR-expressing dopamine neurons. Further, we will use a Cre-dependent adeno-associated virus (AAV) to knock down AmyR expression in VTA dopamine neurons, and examine how this neuronal population contributes to endogenous control of energy balance by amylin. Specific Aim II addresses a critical gap in the literature by evaluating physiological and pharmacological relevance of VTA AmyR in control of palatable food intake and body weight in females, and will test the influence of estradiol on the energy balance effects of VTA AmyR signaling. We will also evaluate how estradiol alters expression of AmyR components in the VTA, thereby providing novel mechanistic insight into central interactions of estradiol and amylin in energy balance control. These studies build upon the PI’s previous K01 and R03 awards by investigating the neural and behavioral mechanisms by which mesolimbic amylin signaling promotes negative energy balance and will address new aspects of this area of research by providing deeper insight into the mechanisms by which VTA amylin signaling controls macronutrient intake as well as sex differences in these effects. Collectively, these studies will provide information on mechanisms of action by which amylin reduces food intake and promotes weight loss, which may in turn facilitate the development of more effective pharmacotherapies for treating obesity.