Metabolic crosstalk through brown fat-enriched secreted factors

 描述（申请人提供）：代谢综合征已成为一种全球流行病，显著增加了2型糖尿病、心血管疾病和非酒精性脂肪肝的风险。棕色脂肪在抵御寒冷方面起着重要作用，有助于全身能量平衡。迄今为止，棕色脂肪的代谢作用主要归因于其刺激非偶联线粒体呼吸的独特能力。分泌因子对外周组织的糖脂代谢和维持全身能量平衡具有不同的作用。脂肪组织激素，如瘦素和脂联素，肠源性成纤维细胞生长因子和肌细胞因子感知营养状态并协调细胞代谢的关键方面。棕色脂肪细胞是否通过分泌因子参与其他代谢组织来调节体内营养和能量代谢尚不清楚。在初步研究中，我们确定了一种新的棕色脂肪富集分泌因子，是高度诱导棕色脂肪细胞分化。利用功能获得和丧失的小鼠模型，我们确定了这种棕色脂肪因子调节全身葡萄糖和脂质代谢。在这个建议中，我们将测试我们的核心假设，即棕色脂肪分泌 因子在代谢串扰中起核心作用。在目标1中，我们计划确定棕色脂肪因子在产热和肥胖过程中代谢适应的作用。在目标2中，我们将评估这种分泌因子的代谢作用机制。在目标3中，我们将评估脂肪因子表达升高在多大程度上保护小鼠免受饮食诱导的代谢紊乱。我们提出的工作将为棕色脂肪在内分泌信号传导中以前未被认识的作用提供见解，并为未来的治疗开发产生关键的临床前数据。

 DESCRIPTION (provided by applicant): Metabolic syndrome has become a global epidemic that dramatically increases the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Brown fat plays an important role in the defense against cold and contributes to whole body energy balance. To date, the metabolic action of brown fat has been primarily attributed to its unique ability to stimulate uncoupled mitochondrial respiration. Secreted factors exert diverse effects on carbohydrate and lipid metabolism in peripheral tissues and the maintenance of systemic energy homeostasis. Adipose tissue hormones, such as leptin and adiponectin, gut-derived fibroblast growth factors, and myokines sense nutrient status and coordinate key aspects of cellular metabolism. Whether brown adipocytes engage other metabolic tissues through secreted factors to regulate nutrient and energy metabolism in the body is unknown. In preliminary studies, we identified a novel brown fat-enriched secreted factor that is highly inducible during brown adipocyte differentiation. Using gain and loss of function mouse models, we established that this brown adipokine regulates whole body glucose and lipid metabolism. In this proposal, we will test our central hypothesis that brown fat secreted factors play a central role in metabolic crosstalk. In Aim 1, we plan to define the role of brown adipokine in metabolic adaptation during thermogenesis and in obesity. In Aim 2, we will evaluate the mechanisms underlying the metabolic action of this secreted factor. In Aim 3, we will assess the extent to which elevated adipokine expression protects mice from diet-induced metabolic derangements. Our proposed work will provide insights into a previously unrecognized role of brown fat in endocrine signaling and generate critical preclinical data for future therapeutic development.