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

PGC-1a 激活化合物刺激棕色和米色脂肪的机制

• 批准号: 9038360
• 负责人: Amy Katherine Rines
• 金额: $ 4.63万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-02-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038360
• 关键词: Acetylation; Acetyltransferase; Address; Adipocytes; Adipose tissue; Affect; American Medical Association; Amino Acids; Anti-Obesity Agents; Area; Brown Fat; Burn injury; Cardiovascular Diseases; Cell Respiration; Characteristics; Chronic Disease; Cyclic AMP; Data; Deacetylation; Developing Countries; Development; Diabetes Mellitus; Disease; Energy Metabolism; Equilibrium; Fatty acid glycerol esters; Gene Expression; Genes; Glucose; Goals; Health; Health Care Costs; Heating; High Fat Diet; Human; Incidence; Knockout Mice; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Mus; Names; Obesity; Oxygen Consumption; Peroxisome Proliferation; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Physiological; Physiology; Public Health; Research; Resistance; Role; Signal Transduction; Starvation; Stress; Structure; Testing; Therapeutic; Therapeutic Agents; United States; adipocyte biology; base; design; economic cost; fatty acid oxidation; follow-up; glucose tolerance; high throughput screening; in vivo; innovation; insulin tolerance; kinase inhibitor; knock-down; lipid metabolism; metabolic phenotype; mitochondrial metabolism; novel; novel therapeutics; oxidation; receptor; research study; response; therapeutic target

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.

描述（由申请人提供）：肥胖是发达国家和发展中国家的重大公共卫生负担，导致其他几种慢性疾病的发生，包括糖尿病、心血管疾病和癌症。由于肥胖的经济和健康成本不断增长，发现作为抗肥胖疗法的新药是研究的关键领域。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γ辅激活因子-1？（PGC-1？？）是一种代谢调节剂，在冷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，其中通过乙酰转移酶氨基酸合成的一般控制5（GCN 5）进行的乙酰化导致其活性降低。我们的实验室已经进行了高通量筛选，以确定新的药物，可以改变乙酰化状态的PGC-1？？以寻找治疗肥胖及其相关疾病的新疗法。我们已经鉴定了一种化合物，我们将其命名为化合物22，它能有效地使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？脱乙酰化和能量消耗。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; 2）阐明化合物22对原代棕色和米色脂肪细胞中代谢的作用，以及这些作用是否依赖于GCN 5; 3）描述化合物22对小鼠中棕色和米色脂肪生理学和肥胖的体内作用，并发现这些作用的机制是否通过GCN 5抑制发生。对于目标1，我们将确定化合物22是直接抑制GCN 5还是通过激酶间接抑制GCN 5。对于目标2，我们将研究化合物22对棕色和米色脂肪细胞中线粒体代谢的影响，有和没有cAMP刺激和GCN 5敲低。在目标3中，我们将用化合物22处理对照和棕色和米色脂肪特异性UCP 1-Cre GCN 5敲除小鼠，有和没有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是否可以表现为抗肥胖治疗剂。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型药物来刺激氧化代谢和能量消耗并减少肥胖。