Signalling pathways regulating adipose tissue thermogenesis

过去十年的发现改变了我们理解脂肪的方式。我们现在知道，脂肪不仅仅是一种被动的能量储存，还可以调节新陈代谢，有趣的是，它可以通过产生热量的过程成为能量消耗的主要来源，这被称为产热。棕色脂肪现在被认为是一种独特的脂肪，而米色脂肪是在经典的白色脂肪中发现的，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刺激人类和小鼠增加产热，但这一过程是如何调节的尚不清楚，也是本研究的主题。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，一种叫做caspase 8的蛋白质在脂肪组织和产热过程中可能很重要。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，以及3)确定炎症信号在脂肪组织产热中的作用。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，我们将使用细胞培养中的脂肪细胞。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caspase 8在产热中的作用，我们将使用仅在脂肪组织中敲除caspase 8的小鼠。动物将被喂食标准食物或西式高脂肪食物，以研究在基础条件和热量过剩条件下发生的情况。动物也将被安置在舒适或寒冷的温度下，以分析在最小和增加刺激下的新陈代谢和产热测量。为了确定caspase 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caspase 8敲除小鼠的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激活炎症的小鼠或细胞，以确定这是否调节代谢。动物将被喂食食物或高脂肪食物，并在舒适或寒冷的温度下饲养，以评估体重增加，能量消耗和核心体温。这项工作将确立caspase 8和炎症信号通路在脂肪组织生物学和产热中的新作用，并确定这些通路之间的相互作用。这项工作将为理解脂肪组织产热在全身生理学中的有趣现象的下一个主要步骤奠定基础。

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.