Role of SIK3 in PKA/mTORC1 regulation of adipose browning

SIK3 在 PKA/mTORC1 调节脂肪褐变中的作用

• 批准号: 10736962
• 负责人: SHEILA COLLINS
• 金额: $ 54.08万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736962
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Affect; Agonist; Amino Acids; Behavioral; Biogenesis; Biology; Body Temperature; Body fat; Body mass index; Brown Fat; Calories; Cardiometabolic Disease; Cardiovascular Diseases; Cell Culture Techniques; Cells; Chronic; Chronic Disease; Complex; Consumption; Country; Critical Pathways; Cyclic AMP; Cyclic AMP Receptor Protein; Cyclic AMP-Dependent Protein Kinases; Data; Desire for food; Disease; Economics; Energy Metabolism; Epidemic; Event; FDA approved; FRAP1 gene; Fatty Acids; Fatty acid glycerol esters; Gatekeeping; Gene Expression; Gene Expression Profile; Genes; Genetic Models; Genetic Transcription; Glucose; Goals; HDAC4 gene; Histone Deacetylase; In Vitro; Incidence; Individual; Insulin Resistance; Isoproterenol; Knockout Mice; Knowledge; Life Style; Link; Location; Medical; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Overweight; PPAR gamma; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology Study; Phosphorylation; Phosphorylation Site; Population; Production; Proteins; Protons; Public Health; Quality of life; Receptor Activation; Receptor Signaling; Regulation; Research; Respiration; Risk; Rodent; Role; Safety; Signal Pathway; Signal Transduction; Sirolimus; Stable Isotope Labeling; Sympathetic Nervous System; Testing; Therapeutic; Tissue Model; Triglycerides; Work; absorption; beta-adrenergic receptor; cardiometabolic risk; cold temperature; cost; diet-induced obesity; economic impact; experimental study; genetic signature; genome-wide; improved; in vivo; inhibitor; insulin sensitivity; knock-down; link protein; metabolic phenotype; metabolic respiration; novel strategies; obesity treatment; overexpression; p38 Mitogen Activated Protein Kinase; pharmacologic; phosphoproteomics; prevent; programs; recruit; response; salt-inducible kinase; small hairpin RNA; small molecule; uncoupling protein 1

Project Summary: . Obesity is at epidemic proportions in the US. Over 60% of the population is either overweight (Body Mass Index [BMI] ≥25 to <30 kg/m2) or obese (BMI ≥30 kg/m2), placing them at risk for a large number of chronic diseases, including insulin resistance, metabolic syndrome, and type 2 diabetes. The annual costs of obesity exceed $100 billion, making it one of the most significant public health and economic issues facing the country. Unfortunately, the treatment of obesity is unsatisfactory. Lifestyle and behavioral approaches have a modest, and often transient, effect while FDA-approved therapeutic options targeting appetite or fat absorption have poor tolerability and, in some cases, safety concerns. Thus, there is a critical need for novel approaches to treat obesity. Agents acting via peripheral mechanisms to increase energy expenditure would be valuable. The sympathetic nervous system (SNS) is well-known as an activator of brown adipose tissue (BAT) and the “browning” of cells in white adipose tissue (WAT) depots to increase uncoupled mitochondrial respiration and energy expenditure. Our earlier work established signaling cascades from β-adrenergic receptors (βARs)  cAMP  protein kinase A (PKA)  p38 MAP kinase (MAPK), and also from PKA to mTORC1. These downstream signaling modules are key to drive the transcription of brown adipocyte genes such as uncoupling protein-1 (UCP1), PPAR-gamma coativator-1α (PGC-1α), and the broader program of mitochondrial biogenesis. The Scientific Premise of this project is based upon our identification of substrates of PKA- activated mTORC1 that convey the brown-adipose promoting machinery, and we will determine their molecular mechanisms. Our long-term goal is to define signaling pathways that are critical to metabolic and cardiovascular disease and, using this knowledge, to target pivotal components of these signaling pathways to prevent or reverse the diseases.

项目摘要：。 肥胖症在美国处于流行比例。超过60％的人口要么超重（体重 指数[BMI]≥25至<30 kg/m2）或肥胖（BMI≥30kg/m2），使它们面临大量慢性的风险 疾病，包括胰岛素抵抗，代谢综合征和2型糖尿病。肥胖的年费 超过1000亿美元，使其成为该国面临的最重大的公共卫生和经济问题之一。 不幸的是，肥胖的治疗是不令人满意的。生活方式和行为方法有一个谦虚的 而且通常是短暂的，效果是针对靶向食欲或脂肪滥用的FDA批准的治疗选择 耐受性差，在某些情况下也是安全问题。那是对新颖方法的迫切需求 治疗肥胖。通过外围机制作用以增加能量消耗的代理人将是有价值的。这 交感神经系统（SNS）众所周知是棕色脂肪组织（BAT）和 白色脂肪组织（WAT）沉积物中细胞的“褐变”，以增加线粒体呼吸和 能源支出。我们较早的工作从β-肾上腺素能受体（βARS）建立了信号级联。 CAMP蛋白激酶A（PKA）p38 MAP激酶（MAPK）以及从PKA到MTORC1。这些 下游信号传导模块是驱动棕色脂肪细胞基因（例如解偶联）转录的关键 蛋白-1（UCP1），PPAR-GAMMA COATIVATOR-1α（PGC-1α）和线粒体更广泛的程序 生物发生。该项目的科学前提是基于我们对PKA-底物的识别。 激活的MTORC1传达了棕色不能糖的促进机械，我们将确定它们的分子 机制。我们的长期目标是定义对代谢至关重要的信号通路 心血管疾病，并使用这些知识将这些信号通路的关键组件靶向 预防或扭转疾病。