Signalling pathways regulating adipose tissue thermogenesis

过去十年的发现改变了我们对脂肪的理解。脂肪不仅仅是一种被动的能量储存，我们现在知道脂肪可以调节新陈代谢，而且有趣的是，它可以通过产生热量的过程（称为产热）成为能量消耗的主要来源。棕色脂肪现在被认为是一种独特的脂肪类型，而米色脂肪存在于经典的白色脂肪中，但与棕色脂肪有一些相似之处。 值得注意的是，棕色和米色脂肪可以被刺激以增加人类和小鼠的产热作用，但这一过程是如何调节的仍然不清楚，这也是这项工作的主题。 这项研究计划的长期目标是确定调节脂肪产热的途径。 我们的初步数据表明，一种名为半胱天冬酶8的蛋白质可能在脂肪组织和产热中很重要。 因此，我们的短期目标是1）确定caspase 8如何调节产热，2）确定caspase 8在调节炎症中的作用，3）建立脂肪组织产热中炎症信号传导的作用。 为了研究信号通路在全身生理和产热中的作用，我们将使用基因敲除小鼠。 为了研究脂肪中信号通路的孤立效应，我们将使用在细胞培养中生长的脂肪细胞。 我们将敲除小鼠体内的信号蛋白，并用抑制剂处理培养的脂肪细胞，以确定不同信号通路在代谢中的作用。 为了确定半胱天冬酶8在产热中的作用，我们将使用仅在脂肪组织中敲除半胱天冬酶8的小鼠。动物将被喂食标准饲料或西式高脂肪饮食，以研究在基础条件和热量过量条件下会发生什么。动物也将在舒适或寒冷的温度下饲养，以分析在最小和增加刺激下的代谢和产热测量。 为了确定胱天蛋白酶8是否调节脂肪中的炎症信号，我们将测量这些脂肪特异性胱天蛋白酶8敲除小鼠脂肪中炎症信号的激活。 我们还将研究敲除caspase 8但激活脂肪中炎症信号的小鼠，以确定caspase 8是否通过控制炎症来调节代谢。 最后，我们还将研究炎症信号和具有活化炎症的小鼠或细胞，以确定这是否调节代谢。 动物将喂食普通饲料或高脂肪饲料，并饲养在舒适或寒冷的温度下，以评估体重增加、能量消耗和核心体温。 这项工作将建立新的作用，基本的caspase 8和炎症信号通路在脂肪组织生物学和产热，并确定这些途径之间的相互作用。这项工作将形成的基础，为下一步的主要步骤，在了解有趣的现象，脂肪组织产热在全身生理学。

Discoveries over the past decade have changed the way we understand fat. More than just a passive energy store, we now know that fat can regulate metabolism, and, intriguingly, can be a major source of energy expenditure through the process of generating heat, known as thermogenesis. Brown fat is now recognized as a unique type of fat, while beige fat is found within classic white fat but has some similarities to brown fat. Notably, brown and beige fat can be stimulated to increase thermogenesis in humans and mice, but how this process is regulated remains unclear and is the subject of this work. The long term objective of this research program is to identify pathways regulating thermogenesis in fat. Our preliminary data suggest that a protein called caspase 8 could be important in adipose tissue and thermogenesis. Thus, our short term goals are 1) to determine how caspase 8 regulates thermogenesis, 2) identify the role of caspase 8 in regulating inflammation, and 3) establish the role of inflammatory signaling in adipose tissue thermogenesis. To study the role of signaling pathways in whole body physiology and heat production, we will use knockout mice. To study the isolated effects of signaling pathways in fat, we will use fat cells grown in cell culture. We will knockout signaling proteins in mice and treat cultured adipocyte cells with inhibitors to determine the role of different signaling pathways in metabolism. To determine the role of caspase 8 in thermogenesis, we will use mice with caspase 8 knocked out only in fat tissue. Animals will be fed a standard chow diet or a Western-style high fat diet to study what happens under basal conditions and conditions of caloric excess. Animals will also be housed at comfortable or cold temperatures to analyze measures of metabolism and heat production under both minimal and increased stimulation. To identify whether caspase 8 regulates inflammatory signaling in fat, we will measure activation of inflammatory signaling in fat from these fat-specific caspase 8 knockout mice. We will also study mice with knockout of caspase 8 but activation of inflammatory signaling in fat, to determine if caspase 8 regulates metabolism by controlling inflammation. Finally, we will also study inflammatory signaling and mice or cells with activated inflammation to determine if this regulates metabolism. Animals will be fed chow or high fat diet, and housed at comfortable or cold temperature, to be assessed for weight gain, energy expenditure and core body temperature. This work will establish new roles for the fundamental caspase 8 and inflammatory signaling pathways in adipose tissue biology and thermogenesis, and identify interactions between these pathways. This work will form the basis for the next major step in understanding the intriguing phenomenon of adipose tissue thermogenesis in whole body physiology.