Genetic approaches to study cytokine control of metabolism

研究细胞因子对代谢控制的遗传学方法

• 批准号: 7967697
• 负责人: Lothar Hennighausen
• 金额: $ 49.48万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967697
• 关键词: Androgen Receptor; Androgens; Appearance; Body Weight decreased; Body fat; Cell Proliferation; Data; Event; Fatty Liver; Fatty acid glycerol esters; Female; Fiber; Genes; Genetic; Genetic Programming; Genetic Transcription; Goals; Growth; Hematopoietic; Interleukins; Knockout Mice; Laboratories; Link; Liver; Liver diseases; Maintenance; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Development; Obesity; Pathway interactions; Physiological; Physiology; Prolactin; Regulation; Reporting; Role; STAT5A gene; Signal Transduction; Skeletal Muscle; Somatotropin; Weight; Weight Gain; blood glucose regulation; cell type; cytokine; fatty acid oxidation; hormone regulation; male; mammary epithelium; mouse model; muscle form; novel; postnatal; skeletal muscle growth; transcription factor

During this reporting period the Laboratory of Genetics and Physiology has made progress in the understanding of mechanisms used by cytokines to control the physiology of muscle and the involvement of cytokines in regulating metabolic processes. Muscle composition and metabolism STAT5 in the muscle is required for postnatal growth and glucose homeostasis, indicating that STAT5 controls the maintenance of muscle mass and function. Histological and gene profiling data revealed reduced muscle mass, an alteration in fiber type composition and decreased activity in mice with a muscle-specific deletion of STAT5 (MKO). This was most pronounced in the quadriceps, a muscle that is composed almost exclusively of type II fibers. This muscle displayed increased expression of type I fiber genes and de novo appearance of type I fibers in mice with muscle-specific deletion of STAT5. We were able to identify the androgen receptor as the critical gene whose expression is regulated directly by STAT5. This demonstrates a novel link between growth hormone signaling, androgen action in muscle cells and muscle physiology. Fatty acid oxidation in muscle Analysis of STAT5 regulated transcription in muscle tissue further revealed a role of STAT5 in fatty acid oxidation as the expression of several genes were found to depended on STAT5. STAT5 MKO female mice revealed decreased body weight, lean mass and soleus weight at 2.5 months old. However, the mice showed increased body weight, lean mass, quadriceps and soleus weight at 20 months old. Stat5 MKO female mice revealed increased fat mass and body fat accumulation at 20 months old. Fatty acid oxidation rate in soleus was increased at 2.5 months old, but it was decreased at 20 months old in STAT5 MKO female mice. STAT5 MKO male mice also revealed increased fat mass and body fat accumulation at 20 months old. Those mice also revealed decreased fatty acid oxidation rate in soleus. We propose that a decrease in fatty acid oxidation contributes to the increased fat mass and body fat accumulation in old mice. We are currently investigating the specific mechanisms involved in the regulation of these processes and the metabolic consequences of signaling events that are regulated by the transcription factor STAT5.

在本报告期内，遗传学和生理学实验室在了解细胞因子用于控制肌肉生理学的机制以及细胞因子参与调节代谢过程方面取得了进展。 肌肉组成和新陈代谢 肌肉中的 STAT5 是出生后生长和葡萄糖稳态所必需的，这表明 STAT5 控制着肌肉质量和功能的维持。 组织学和基因分析数据显示，肌肉特异性缺失 STAT5 (MKO) 的小鼠肌肉质量减少、纤维类型组成发生改变以及活动减少。 这在股四头肌中最为明显，股四头肌几乎完全由 II 型纤维组成。 在肌肉特异性缺失 STAT5 的小鼠中，该肌肉显示出 I 型纤维基因表达增加，并且 I 型纤维从头出现。 我们能够确定雄激素受体是关键基因，其表达受 STAT5 直接调节。 这证明了生长激素信号传导、肌肉细胞中雄激素的作用和肌肉生理学之间的新联系。 肌肉中的脂肪酸氧化 对肌肉组织中 STAT5 调节转录的分析进一步揭示了 STAT5 在脂肪酸氧化中的作用，因为发现多个基因的表达依赖于 STAT5。 STAT5 MKO 雌性小鼠在 2.5 个月大时体重、瘦肉质量和比目鱼肌重量均有所下降。然而，小鼠在 20 个月大时体重、瘦体重、股四头肌和比目鱼肌重量均有所增加。 Stat5 MKO 雌性小鼠在 20 个月大时发现脂肪量和体内脂肪积累增加。 STAT5 MKO 雌性小鼠比目鱼肌脂肪酸氧化率在 2.5 月龄时增加，但在 20 月龄时下降。 STAT5 MKO 雄性小鼠在 20 个月大时也显示出脂肪量和体内脂肪积累增加。 这些小鼠还显示比目鱼肌的脂肪酸氧化率降低。 我们认为脂肪酸氧化的减少有助于老年小鼠脂肪量的增加和体内脂肪的积累。 我们目前正在研究调节这些过程的具体机制以及受转录因子 STAT5 调节的信号事件的代谢后果。