ABLATION OF HYPOTHALAMIC POMC/CART NEURONS

肥胖是美国的一个主要健康问题，影响着很大一部分人口。它可能导致严重的疾病，如心力衰竭、中风和糖尿病。为了找到预防和治疗这种严重疾病的最佳方法，需要对体重的动态平衡调节有更详细的了解。下丘脑中的POMC神经元已被证明在体重稳态中起着关键作用。黑素皮质素抑制进食，对适当的体重平衡是必不可少的，因为黑素皮质素信号缺乏的小鼠是肥胖的。β-内啡肽对体重稳态的影响还不是很清楚。令人惊讶的是，我们的初步结果表明，缺乏β-内啡肽的小鼠也会肥胖。这笔赠款的第一个目标是建立β-内啡肽缺陷小鼠肥胖的机制，并确定这种肥胖是否与MC4受体缺陷小鼠相加。NPY调节这些神经元释放α-MSH和β-内啡肽，阿片类拮抗剂已被证明可以阻断NPY刺激的食物摄取。因此，我们计划测试NPY的作用需要β-内啡肽的假设，并预测缺乏β-内啡肽的小鼠在NPY刺激的摄食中将出现缺陷。下丘脑腹基底部对体重动态平衡和瘦素受体的高水平表达具有抑制作用。POMC和NPY神经元在该区域均有胞体，并表达瘦素受体。除了黑素皮质素，POMC神经元还表达CART，一种被证明有效地抑制摄食的递质，并被预测在体重稳态中发挥重要作用，以及潜在的未知递质。我们假设POMC神经元中的其他递质，除了黑素皮质素外，对体重稳态和瘦素的作用也很重要。为了测试这一点，我们建议通过专门消融成年小鼠的POMC神经元来移除所有通过这些POMC神经元的信号。然后将这些小鼠的体重稳态和瘦素功能与仅缺乏POMC信号的小鼠进行比较。

Obesity is a major health problem in the United States affecting a large portion of the population. It can lead to serious diseases such as heart failure, stroke and diabetes. A more detailed understanding of the homeostatic regulation of weight is required to find the best method of both preventing and treating this serious disease. POMC neurons in the hypothalamus have been demonstrated to play a critical role m weight homeostasis. Melanocortins inhibit feeding and are essential for appropriate weight homeostasis as mice deficient in melanocortin signaling are obese. The effects of beta-endorphin on weight homeostasis are less clear. Surprisingly, our preliminary results indicate that mice lacking beta-endorphin are also obese. The first goal of this grant is to establish the mechanism of the obesity in beta-endorphin deficient mice and to determine whether this obesity is additive with MC4 receptor deficient mice. NPY modulates the release of alpha-MSH and beta-endorphin from these neurons, and opioid antagonists have been shown to block NPY stimulated food intake. We therefore plan to test the hypothesis that beta-endorphin is required for the action of NPY and predict that mice lacking beta-endorphin will be deficient in NPY- stimulated feeding. The ventrobasal hypothalamus has an inhibitory tone on weight homeostasis and high levels of expression of leptin receptors. Both POMC and NPY neurons have cell bodies in this region and express leptin receptors. In addition to the melanocortins, POMC neurons also express CART, a transmitter shown to potently inhibit feeding and predicted to play an important role in weight homeostasis, as well as potentially unidentified transmitters. We hypothesize that other transmitters in the POMC neurons, aside from the melanocortins, are important for weight homeostasis and leptin action. To test this, we propose to remove all signaling through these POMC neurons by specifically ablating the POMC neurons in adult mice. Weight homeostasis and leptin function in these mice will then be compared to mice deficient solely in POMC signaling.