MICT1 function in thermogenesis

肥胖已经成为一种全球流行病，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 通过非颤抖的生热作用。在成人中发现蝙蝠/蝙蝠样组织的存在 对蝙蝠生物学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，我们发现了一个长度为76aa的新的微蛋白，它在BAT中的表达水平高于其他基因 组织，并在寒冷暴露时诱导。影响蛋白质-蛋白质的微蛋白在一般功能中的作用 信号分子之间的相互作用。我们的微蛋白含有蛋白质的共识对接基序 磷酸酶2B。我们的初步研究表明，这种微蛋白在分化的蝙蝠中过表达 细胞增加了氧耗率(OCR)，而击倒降低了基础和Forsklin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 这种微蛋白在蝙蝠细胞中的过度表达。为了证明它的生理功能，我们生成了 条件性基因敲除小鼠和转基因小鼠在UCP1细胞和 脂肪细胞。我们认为，我们的微蛋白与PP2B相互作用，调节经典的b-肾上腺素能 下游信号转导，并增强PKA活性，促进产热。目标1是研究它的影响 分化的棕色脂肪细胞在培养中的产热作用。目标2是剖析其生物化学基础。 对生热有促进作用。最后，目标3是通过损失-3来评价其在体内的生热功能。 以及对小鼠的功能获得性研究。这项研究可能会让我们设计出小分子疗法来 增加生热作用，预防肥胖，改善未来的胰岛素敏感性。

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.