LIFR-alpha/JAK/STAT3-dependent Adipose Inflammation Contributes to Obesity-Associated NAFLD - Resubmissi

LIFR-alpha/JAK/STAT3 依赖性脂肪炎症导致肥胖相关 NAFLD - Resubmissi

基本信息

批准号：
10364225
负责人：
Rodney E Infante
金额：
$ 51.73万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364225
关键词：
Adenylate Cyclase Adipocytes Adipose tissue Affect Animals Atlases Blood Vessels Cell Line Cells Complex Cyclic AMP Cytokine Signaling Data Dependence Development Diet Equilibrium Family Fatty acid glycerol esters Genetic Genetic Models Hepatic High Fat Diet Immune Immune signaling Inflammation Inflammatory Interleukin-6 Knockout Mice LIF gene LIFR gene Lipid Mobilization Lipolysis Liver Mediating Mediator of activation protein Messenger RNA Metabolic Modeling Molecular Mus Obesity Pathway interactions Phenotype Phosphorylation Recombinants Regulation Resolution Role STAT3 gene Signal Pathway Signal Transduction Steatohepatitis Techniques Triglycerides Wild Type Mouse adipokines base cell type comorbidity counterregulation cytokine diet-induced obesity in vitro Assay inhibitor leukemia inhibitory factor receptor mouse model non-alcoholic fatty liver disease novel obesity development receptor response single-cell RNA sequencing transcriptome transcriptome sequencing

项目摘要

ABSTRACT Although adipose inflammation is associated with obesity, its role in reprogramming adipocytes and other cells in adipose towards the development of obesity’s metabolic comorbidities including steatosis remain unclear. The complex intracellular (stromal, vascular, immune, and adipocyte) interactions within adipose tissue ultimately regulate its size by balancing adipocyte triacylglyceride (TAG) lipolysis and synthesis. The inflammatory signaling of and between these cell types may also influence adipocyte responses to cAMP modulators. To understand the convergence of these interactions, we previously identified cytokine leukemia inhibitory factor (LIF) as a secretory molecule that increased adipose inflammation and lipolysis. Wild type mice on a high fat diet (HFD) demonstrated 7-fold higher LIF and IL-6 adipose mRNA than matched animals on normal diets. When recombinant LIF was administered to wild-type mice, it caused >50% loss of fat mass through JAK/STAT3- dependent reprogramming of adipose tissue, increasing lipolysis and amplifying inflammation by altering the expression of other cyto/adipokines. JAK inhibitor treatment of rLIF-administered mice suppressed adipose loss through 1) inhibition of adipose inflammation as determined by decreased STAT3 phosphorylation, 2) decreased adipocyte lipolysis, and 3) inhibition of cyto/adipokine changes. To establish the importance of this signaling pathway to adipose inflammation, we selectively silenced LIF receptor (LIFR-α, gene LIFR) or STAT3 in adipocytes and assessed murine development in diet-induced obesity. Both models had decreased adipose inflammation resulting in a 50% increase in adipose mass and a ~75% reduction in total hepatic TAG levels compared to controls, limiting non-alcoholic fatty liver disease (NAFLD) and steatohepatitis in these mice. Conversely, with adipocyte silencing of the JAK/STAT counter-regulator SOCS3 in mice on HFDs, we observed the opposite phenotype with a ~30% reduction in adipose mass compared to controls. We hypothesize that a LIFR-α/JAK/STAT3-dependent Cytokine-Adipose-Hepatic Axis facilitates adipose inflammation, leading to increased lipolysis and altered expression of other cyto/adipokines. The activation of this axis limits adipose expansion, resulting in TAG mobilization from adipose to the liver and ultimately contributing to NAFLD/steatohepatitis. This inflammatory-driven axis also affects adipose responses to systemic metabolic change, sensitizing adipocytes to lipolytic regulation by other cAMP modulators. Finally, we present preliminary data that the IL-6 family of cytokines signal through JAK/STAT3 inducing the expression of adenylyl cyclase 5 (ADCY5) to reprogram adipocytes in regulating lipid mobilization. SA1 will evaluate the contribution of the LIFR-α/JAK/STAT3 signaling cascade in adipocytes to the Cytokine-Adipose-Hepatic Axis. SA2 will use a genetics-based approach to verify that cytokine-mediated reprogramming of adipocytes in promoting lipid mobilization requires ADCY5 function. SA3 will use single cell RNA-Seq techniques in our multiple mouse models to identify non-adipocyte contributors to inflammation-regulated obesity and NAFLD.

抽象的尽管脂肪炎症与肥胖有关，但其在脂肪细胞和其他细胞重编程中的作用脂肪对包括脂肪变性在内的肥胖代谢合并症的发展仍不清楚。脂肪最终组织内复杂的细胞内（基质、血管、免疫和脂肪细胞）相互作用通过平衡脂肪细胞三酰甘油（TAG）脂肪分解和炎症信号传导来调节其大小。这些细胞类型之间的差异也可能影响脂肪细胞对 cAMP 调节剂的反应。综合这些相互作用，我们之前将细胞因子白血病抑制因子（LIF）确定为增加高脂肪饮食（HFD）野生型小鼠脂肪炎症和脂肪分解的分泌分子。 LIF 和 IL-6 脂肪 mRNA 比正常饮食的匹配动物高 7 倍。将重组 LIF 给予野生型小鼠，它通过 JAK/STAT3-导致脂肪量减少 > 50% 脂肪组织的依赖性重编程，通过改变 rLIF 给药小鼠的其他细胞/脂肪因子的表达抑制了脂肪损失。通过 1) 通过减少 STAT3 磷酸化来抑制脂肪炎症，2) 减少脂肪细胞脂肪分解，以及 3) 抑制细胞/脂肪因子变化以确定该信号传导的重要性。为了研究脂肪炎症的途径，我们选择性地沉默了 LIF 受体（LIFR-α，基因 LIFR）或 STAT3 脂肪细胞并评估了饮食诱导的肥胖小鼠的发育，两种模型的脂肪含量均有所减少。炎症导致脂肪量增加 50%，肝脏总 TAG 水平减少约 75% 与对照组相比，限制了这些小鼠的非酒精性脂肪肝病（NAFLD）和脂肪性肝炎。离线时，通过 HFD 小鼠的脂肪细胞沉默 JAK/STAT 反调节因子 SOCS3，我们观察到相反的表型，与对照组相比，脂肪量减少约 30%。 LIFR-α/JAK/STAT3 依赖性细胞因子-脂肪-肝轴促进脂肪炎症，导致增加脂肪分解并改变其他细胞/脂肪因子的表达该轴的激活限制脂肪。扩张，导致 TAG 从脂肪动员到肝脏，最终有助于 NAFLD/脂肪肝炎。这种炎症驱动的轴也会影响脂肪对全身代谢的反应。改变，使脂肪细胞对其他 cAMP 调节剂的脂肪分解调节敏感。数据表明，IL-6 细胞因子家族通过 JAK/STAT3 发出信号，诱导腺苷酸环化酶 5 的表达 SA1 将评估脂肪细胞中 LIFR-α/JAK/STAT3 信号级联对细胞因子-脂肪-肝轴的贡献，SA2 将使用基于遗传学的方法来验证细胞因子。 -介导的脂肪细胞重编程促进脂质动员需要 ADCY5 功能的 SA3 将在我们的多个小鼠模型中使用单细胞 RNA-Seq 技术来识别。非脂肪细胞导致炎症调节性肥胖和 NAFLD。