MICT1 function in thermogenesis

MICT1 在生热作用中的功能

• 批准号: 10570388
• 负责人: Hei Sook Sul
• 金额: $ 51.93万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570388
• 关键词: A kinase anchoring protein; Ablation; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Affect; Agonist; Amino Acid Motifs; Binding; Biochemical; Biology; Blood Vessels; Body Temperature; Brown Fat; Calcineurin; Cell membrane; Cells; Chronic Disease; Co-Immunoprecipitations; Consensus; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Disease Management; Docking; Epidemic; FK506; Forskolin; Future; Gene Expression; Gene Proteins; Generations; Glucose; Glucose Clamp; Health; Homeostasis; Hyperinsulinism; Insulin; Insulin Resistance; Knockout Mice; Length; LoxP-flanked allele; Measures; Mediating; Membrane; Metabolic Diseases; Metabolic syndrome; Mitochondria; Mus; Myristic Acylation Site; N-terminal; Names; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obesity; Organ; Oxygen Consumption; Phosphorylation; Phosphotransferases; Physiological; Process; Protein Dephosphorylation; Proteins; Reporter; Research; Resistance; Role; Signal Transduction; Signaling Molecule; Testing; Thermogenesis; Time; Tissues; Transgenic Mice; Variant; adipocyte differentiation; conditional knockout; design; gain of function; genome-wide; improved; in vitro Assay; in vitro activity; in vivo; inhibitor; insulin sensitivity; interest; knock-down; live cell imaging; loss of function; mutant; myristoylation; new therapeutic target; obesity prevention; overexpression; prevent; promoter; protein protein interaction; sensor; small hairpin RNA; small molecule therapeutics; therapeutic target

Obesity has become a global epidemic and is associated with type 2 diabetes and other chronic diseases. While white adipose tissue is the primary energy storage organ, brown adipose tissue (BAT) dissipates energy through non-shivering thermogenesis. Discovery of the presence of BAT/BAT-like tissues in human adults has generated a considerable interest in BAT biology to design strategies against obesity and insulin resistance. Recently, we have identified a new microprotein of 76 aa in length, highly expressed in BAT compared to other tissues, and is induced upon cold exposure. Microproteins in general function by affecting protein-protein interaction between signaling molecules. Our microprotein contains consensus docking motifs for Protein Phosphatase 2B. Our preliminary studies showed that overexpression of this microprotein in differentiated BAT cells increased oxygen consumption rate (OCR), while knockdown decreased OCR in basal and forskolin stimulated conditions. Moreover, we detected higher PKA activity without changes in cAMP levels upon overexpression of this microprotein in BAT cells. To document its physiological function, we have generated conditional knockout mice and transgenic mice overexpressing the microprotein in UCP1+ cells and in adipocytes. We propose that, our microprotein interacts with PP2B to regulate classic b-adrenergic downstream signaling and potentiates PKA activity for promotion of thermogenesis. Aim 1 is to study its effect on thermogenesis in differentiated brown adipocytes in culture. Aim 2 is to dissect the biochemical basis of its function in promoting thermogenesis. Finally, Aim 3 is to evaluate its in vivo function in thermogenesis by loss- and gain-of function studies in mice. This research may allow us to devise small molecule therapeutics to increase thermogenesis for preventing obesity and improving insulin sensitivity in the future.

肥胖已成为一种全球流行病，并与2型糖尿病和其他慢性疾病有关。 虽然白色脂肪组织是主要的能量储存器官，但棕色脂肪组织（BAT）消耗能量 通过不颤抖的产热作用。发现成人体内存在BAT/BAT样组织， 在BAT生物学中产生了相当大的兴趣，以设计对抗肥胖和胰岛素抵抗的策略。 最近，我们鉴定了一种新的76 aa长的微蛋白，与其他微蛋白相比，其在BAT中高度表达。 组织，并在冷暴露时诱导。微量蛋白一般通过影响蛋白-蛋白 信号分子之间的相互作用。我们的微蛋白含有蛋白质的共有对接基序 磷酸酶2B。我们的初步研究表明，这种微蛋白在分化的BAT中过表达， 细胞增加耗氧率（OCR），而敲低降低OCR基础和毛喉素 刺激的条件。此外，我们检测到更高的PKA活性，而cAMP水平没有变化， 这种微蛋白在BAT细胞中的过度表达。为了记录其生理功能，我们生成了 在UCP1+细胞和UCP2+细胞中过表达微蛋白的条件性基因敲除小鼠和转基因小鼠， 脂肪细胞我们提出，我们的微蛋白与PP2B相互作用，以调节经典的b-肾上腺素能 下游信号传导并增强PKA活性以促进产热。目的一是研究其作用 对培养的分化棕色脂肪细胞产热的影响。目的2是剖析其生物化学基础， 促进产热作用。最后，目的3是通过损失来评估其在产热中的体内功能。 和小鼠的功能获得研究。这项研究可能使我们能够设计小分子疗法， 增加产热作用，以预防肥胖和改善胰岛素敏感性。