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.

肥胖已成为全球流行病，并与 2 型糖尿病和其他慢性病有关。 白色脂肪组织是主要的能量储存器官，而棕色脂肪组织 (BAT) 则消耗能量 通过非颤抖产热。发现成人体内存在 BAT/BAT 样组织 引起了人们对 BAT 生物学的极大兴趣，以设计针对肥胖和胰岛素抵抗的策略。 最近，我们发现了一种长度为 76 个氨基酸的新微生物蛋白，与其他微生物蛋白相比，它在 BAT 中高表达。 组织，并在冷暴露时诱导。微生物蛋白质的一般功能是通过影响蛋白质-蛋白质来发挥作用 信号分子之间的相互作用。我们的微生物蛋白包含蛋白质的共识对接基序 磷酸酶2B。我们的初步研究表明，这种微生物蛋白在分化的 BAT 中过度表达 细胞的耗氧率（OCR）增加，而敲除降低了基础和毛喉素的 OCR 刺激条件。此外，我们检测到更高的 PKA 活性，而 cAMP 水平没有变化 该微生物蛋白在 BAT 细胞中过度表达。为了记录其生理功能，我们生成了 条件敲除小鼠和转基因小鼠在 UCP1+ 细胞和 脂肪细胞。我们提出，我们的微生物蛋白与 PP2B 相互作用来调节经典的 β-肾上腺素能 下游信号传导并增强 PKA 活性以促进生热作用。目标1是研究其效果 培养中分化的棕色脂肪细胞的产热作用。目标 2 是剖析其生化基础 具有促进生热作用。最后，目标 3 是通过损失来评估其在生热作用中的体内功能 和小鼠功能获得研究。这项研究可能使我们能够设计出小分子疗法 增加生热作用，以预防肥胖并提高未来的胰岛素敏感性。