Role of SIK3 in PKA/mTORC1 regulation of adipose browning

项目概要： 肥胖在美国已成为流行病。超过60%的人口超重（体重 指数[BMI] ≥25至<30 kg/m2）或肥胖（BMI ≥30 kg/m2），使他们处于大量慢性 这些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要的公共卫生和经济问题之一。 不幸的是，肥胖症的治疗并不令人满意。生活方式和行为方法有一个适度的， 而且通常是短暂的，而FDA批准的针对食欲或脂肪吸收的治疗选择， 耐受性差，在某些情况下，还有安全性问题。因此，迫切需要新的方法来 治疗肥胖症。通过外周机制起作用以增加能量消耗的试剂将是有价值的。的 众所周知，交感神经系统（SNS）是棕色脂肪组织（BAT）的激活剂， 白色脂肪组织（WAT）贮库中细胞的“布朗宁”，以增加非偶联线粒体呼吸， 能量消耗我们早期的工作建立了β-肾上腺素能受体（β AR）的信号级联反应。 cAMP依赖性蛋白激酶A（PKA）依赖性p38 MAP激酶（MAPK），以及从PKA到mTORC 1。这些 下游信号模块是驱动棕色脂肪细胞基因转录的关键， 蛋白质-1（UCP 1）、PPAR-gamma coativator-1α（PGC-1α）以及线粒体的更广泛的程序。 生物起源该项目的科学预测是基于我们对PKA底物的鉴定， 激活mTORC 1，传递棕色脂肪促进机制，我们将确定它们的分子 机制等我们的长期目标是确定对代谢和 心血管疾病，并利用这一知识，针对这些信号通路的关键组成部分， 预防或逆转疾病。

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.