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

描述（由申请人提供）：肥胖在发达国家和发展中国家都是一个重要的公共健康负担，它导致了其他几种慢性疾病的发病率，包括糖尿病、心血管疾病和癌症。由于肥胖带来的经济和健康成本越来越高，发现抗肥胖药物是一个关键的研究领域。棕色和米色脂肪已被确定为肥胖治疗的可能目标，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。过氧化物酶体增殖激活受体-辅激活因子-1？（PGC-1??）是一种代谢调节剂，在低温刺激下在棕色和米色脂肪中被激活，并起到增加能量消耗和氧化代谢的作用。PGC-1的活性？？可以通过其乙酰化状态进行调节，乙酰化由乙酰转移酶总控制氨基酸合成5 （GCN5）导致其活性降低。我们的实验室进行了高通量筛选，以确定可以改变PGC-1乙酰化状态的新药？？为了找到治疗肥胖及其相关疾病的新方法。我们已经确定了一种化合物，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的产热和氧化代谢基因表达。因此，我们假设化合物22可以通过其对PGC-1的作用作为一种抗肥胖药物。去乙酰化和能量消耗。为了验证这一假设，我们将在本提案中解决三个具体目标：1)确定化合物22抑制GCN5增加PGC-1的机制？？脱乙酰作用;2)阐明化合物22对原代棕色和米色脂肪细胞代谢的影响，以及这些影响是否依赖于GCN5；3)描述化合物22对小鼠褐色和米色脂肪生理和肥胖的体内影响，并发现这些影响是否通过抑制GCN5发生的机制。对于Aim 1，我们将确定化合物22是直接抑制GCN5还是通过激酶间接抑制GCN5。在Aim 2中，我们将研究化合物22对棕色和米色脂肪细胞线粒体代谢的影响，无论是否有cAMP刺激和GCN5敲低。在Aim 3中，我们将用化合物22治疗对照组和棕色和米色脂肪特异性UCP1-Cre GCN5敲除小鼠，无论有无冷应激或高脂肪饮食，并评估它们的代谢和肥胖情况，以确定化合物22是否具有抗肥胖治疗作用。这些研究将揭示化合物22的作用机制，并将证明该化合物是否可以作为一种新的药物来刺激氧化代谢和能量消耗，减少肥胖。

DESCRIPTION (provided by applicant): 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 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.