Mechanisms of brown and beige fat stimulation by a PGC-1a-activating compound

项目描述 肥胖是发达国家和发展中国家的一个重大公共卫生负担， 糖尿病、心血管疾病和癌症等其他几种慢性病的发病率。由于 肥胖带来的日益增长的经济和健康成本，发现作为抗肥胖疗法的新药 是一个重要的研究领域棕色和米色脂肪已被确定为肥胖治疗的可能靶点， 因为这些类型的脂肪组织燃烧脂肪以增加能量消耗并减少脂肪储存。过氧化物酶 增殖激活受体γ共激活因子-1）是一种代谢调节因子， 棕色和米色脂肪与冷刺激和行为增加能量消耗和氧化代谢。 PGC-1 <$的活性可以通过其乙酰化状态进行调节，乙酰化是由 乙酰转移酶氨基酸合成的一般控制5（GCN 5）导致其活性降低。我们 实验室进行了高通量筛选，以确定新的药物，可以改变乙酰化状态的 PGC-1 <$，以寻找肥胖及其相关疾病的新疗法。我们已经确认了一个 化合物，我们将其命名为化合物22，它有效地使PGC-1去乙酰化并激活 棕色和米色脂肪细胞中产热和氧化代谢基因的表达。因此，我们假设 化合物22可以通过其对PGC-1的脱乙酰化和能量的影响作为抗肥胖药物 支出为了验证这一假设，我们将在本提案中提出三个具体目标：1）确定 化合物22抑制GCN 5以增加PGC-1脱乙酰化的机制; 2）阐明化合物22抑制GCN 5以增加PGC-1脱乙酰化的机制。 化合物22对原代棕色和米色脂肪细胞中代谢的影响，以及这些影响是否 3）描述化合物22对棕色和米色脂肪生理学的体内作用， 肥胖小鼠，并发现这些作用的机制是否通过GCN 5抑制发生。为 目的1，我们将确定化合物22是否直接抑制GCN 5或间接抑制GCN 5 通过一个激酶。对于目标2，我们将研究化合物22对线粒体代谢的影响， 有和没有cAMP刺激和GCN 5敲低的棕色和米色脂肪细胞。在目标3中，我们将治疗 对照以及棕色和米色脂肪特异性UCP 1-Cre GCN 5敲除小鼠，用化合物22， 冷应激或高脂肪饮食，并评估它们的代谢和肥胖，以确定化合物22是否可以 起到减肥的作用这些研究将揭示化合物22的作用机制， 并将证明这种化合物是否可以作为一种新型药物来刺激氧化代谢， 能量消耗和减少肥胖。

Project Description Obesity is a significant public health burden in both developed and developing nations that contributes to the incidence of several other chronic diseases including diabetes, cardiovascular disease, and cancer. Due to the growing economic and health costs of obesity, discovering novel drugs that act as anti-obesity therapeutics is a critical area of research. Brown and beige fat have been identified as possible targets for obesity therapy, as these types of adipose tissue burn fat to increase energy expenditure and reduce fat storage. Peroxisome proliferation-activated receptor gamma coactivator-1¿ (PGC-1¿) is a metabolic regulator that is activated in brown and beige fat with cold stimulation and acts to increase energy expenditure and oxidative metabolism. The activity of PGC-1¿ can be modulated through its acetylation status, with acetylation by the acetyltransferase general control of amino acid synthesis 5 (GCN5) leading to a decrease in its activity. Our lab has conducted a high-throughput screen to identify novel drugs that can modify the acetylation status of PGC-1¿ in order to find novel therapies for obesity and its related disorders. We have identified one compound, which we have named compound 22, which effectively deacetylates PGC-1¿ and activates thermogenic and oxidative metabolic gene expression in brown and beige adipocytes. Thus, we hypothesize that compound 22 can act as an anti-obesity drug through its effects on PGC-1¿ deacetylation and energy expenditure. To test this hypothesis, we will address three specific aims in this proposal: 1) determine the mechanism through which compound 22 inhibits GCN5 to increase PGC-1¿ deacetylation; 2) elucidate the effects of compound 22 on metabolism in primary brown and beige adipocytes, and whether these effects depend on GCN5; 3) delineate the in vivo effects of compound 22 on brown and beige fat physiology and obesity in mice, and discover whether the mechanism of these effects occurs through GCN5 inhibition. For Aim 1, we will determine whether compound 22 either directly inhibits GCN5 or inhibits GCN5 indirectly through a kinase. For Aim 2, we will investigate the effects of compound 22 on mitochondrial metabolism in brown and beige adipocytes with and without cAMP stimulation and GCN5 knockdown. In Aim 3, we will treat control and brown and beige fat-specific UCP1-Cre GCN5 knockout mice with compound 22 with and without cold stress or a high fat diet and assess their metabolism and obesity to determine whether compound 22 can behave as an anti-obesity therapeutic. These studies will reveal the mechanisms of action of compound 22, and will demonstrate whether this compound can act as a novel drug to stimulate oxidative metabolism and energy expenditure and reduce obesity.