Immune pathways in adipose thermogenesis

摘要 脂肪组织在代谢和能量平衡以及脂肪细胞的失调中起着核心作用 功能是代谢综合征发病机制的基础。我们的团队有着 识别和表征参与脂肪细胞生物学的重要蛋白质，包括PPARγ、TLE 3和 PSPC 1.最近，我们发现了一种新的脂肪产热活动的生理调节因子：细胞因子 IL 10。这项建议建立在这一发现的基础上，以解决有关监管的重要问题， 全身代谢，脂肪产热，以及免疫细胞和脂肪细胞之间的串扰， 脂肪组织库。刺激脂肪组织产热的调节途径已经被证实是 广泛表征，但能量消耗的限制因素仍然定义不清。我们有 发现在脂肪细胞中通过STAT 3的IL 10信号传导调节产热基因表达， 能量消耗IL 10受体α（IL 10 R α）在成熟脂肪细胞中高度富集，并被诱导 对分化肥胖和衰老的反应。初步数据表明，IL-10信号抑制β- 肾上腺素能信号，并减少ATF和C/EBPβ在产热细胞上的占有率。 基因启动子此外，抑制脂肪组织中IL 10受体α（IL 10 R α）的表达， 反义寡核苷酸（ASOs）对饮食诱导的肥胖具有保护作用，这表明脂肪IL 10 轴可能是治疗靶点。在这里，我们建议进一步定义特定的细胞类型和组织 产生和接收影响代谢的IL-10信号，以阐明IL-10 信号转导调节脂肪细胞基因表达，了解脂肪组织免疫细胞 群体中的调节产热的IL 10。具体目标1是表征脂肪细胞-内源性 IL-10信号在脂肪组织中脂质储存和产热中的作用。具体目标2是定义 IL-10对产热的转录调节机制。具体目标3是描绘 脂肪组织驻留免疫细胞在IL 10调节产热中的作用。

Abstract Adipose tissue plays a central role in metabolic and energy homeostasis, and dysregulation of adipocyte function is fundamental to the pathogenesis of the metabolic syndrome. Our group has a track record of identifying and characterizing important proteins involved in adipocyte biology, including PPARγ, TLE3, and PSPC1. Recently, we uncovered a novel physiological regulator of adipose thermogenic activity: the cytokine IL10. This proposal builds upon this discovery to address important questions regarding the regulation of systemic metabolism, adipose thermogenesis, and the crosstalk between immune cells and adipocytes within adipose tissue depots. Regulatory pathways that stimulate adipose tissue thermogenesis have been extensively characterized, but the limiters of energy expenditure have remained poorly defined. We have discovered that IL10 signaling through STAT3 in adipocytes regulates thermogenic gene expression and energy expenditure. The IL10 receptor alpha (IL10Rα) is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Preliminary data indicate that IL-10 signaling inhibits beta- adrenergic signaling in beige adipocytes, and reduces the occupancy of ATF and C/EBPβ on thermogenic gene promoters. Moreover, inhibiting the expression of the IL10 receptor alpha (IL10Rα) in adipose tissue with antisense oligonucleotides (ASOs) is protective against diet-induced obesity, suggesting that the adipose IL10 axis might be targeted therapeutically. Here we propose to further define the specific cell types and tissues that produce and receive IL-10 signals affecting metabolism, to elucidate the mechanisms by which IL10 signaling regulates adipocyte gene expression, and to understand the roles of adipose tissue immune cell populations in the regulation of thermogenesis by IL10. Specific Aim 1 is to characterize the adipocyte-intrinsic role of IL-10 signaling in lipid storage and thermogenesis in adipose tissue. Specific Aim 2 is to define the mechanisms underlying transcriptional modulation of thermogenesis by IL-10. Specific Aim 3 is to delineate the role of adipose tissue-resident immune cells in the regulation of thermogenesis by IL10.