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.

项目概要： . 肥胖在美国已成为一种流行病，超过 60% 的人口体重超重（体重）。 指数[BMI]≥25至<30kg/m2）或肥胖（BMI≥30kg/m2），使他们面临大量慢性病的风险 疾病，包括胰岛素抵抗、代谢综合征和 2 型糖尿病 肥胖的年度成本。 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，生活方式和行为方法对肥胖的治疗并不令人满意。 效果通常是短暂的，而 FDA 批准的针对食欲或脂肪吸收的治疗方案却具有 耐受性差，在某些情况下还存在安全问题，因此迫切需要新的方法来治疗。 通过外周机制作用来增加能量消耗的药物将是有价值的。 交感神经系统 (SNS) 是众所周知的棕色脂肪组织 (BAT) 激活剂， 白色脂肪组织（WAT）库中的细胞“褐变”，以增加解偶联的线粒体呼吸和 我们早期的工作建立了 β-肾上腺素受体 (βAR) 的信号级联  cAMP → 蛋白激酶 A (PKA) → p38 MAP 激酶 (MAPK)，以及从 PKA 到 mTORC1。 下游信号模块是驱动棕色脂肪细胞基因转录的关键，例如解偶联 Protein-1 (UCP1)、PPAR-gamma cotivator-1α (PGC-1α) 以及更广泛的线粒体程序 该项目的科学前提是基于我们对 PKA 底物的鉴定。 激活传递棕色脂肪促进机制的 mTORC1，我们将确定其分子 我们的长期目标是定义对代谢和代谢至关重要的信号通路。 心血管疾病，并利用这些知识，针对这些信号通路的关键组成部分 预防或逆转疾病。