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。