SNRK(sucrose non-fermenting related kinase)and adipose energy homeostasis

SNRK（蔗糖非发酵相关激酶）与脂肪能量稳态

• 批准号: 8958657
• 负责人: Haiyan Xu
• 金额: $ 41.91万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-28 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958657
• 关键词: Adipocytes; Adipose tissue; Adult; Age; Body fat; Brown Fat; Data; Development; Disease; Energy Intake; Epidemic; Event; Goals; Heating; Homeostasis; Human; Impairment; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Knockout Mice; Lead; Leptin; Light; Lipolysis; Metabolic Diseases; Metabolism; Methods; Mitochondria; Molecular; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obese Mice; Obesity; Organ; Oxygen Consumption; Perinatal; Phosphotransferases; Play; Proteins; Reporting; Research; Risk Factors; Rodent; Role; Signal Pathway; Sucrose; Thermogenesis; Tissues; adipocyte differentiation; base; chemokine; cytokine; insulin signaling; loss of function; macrophage; mouse model; new therapeutic target; novel; novel therapeutics; nutrition; public health relevance; pup; response; sedentary lifestyle; subcutaneous

 DESCRIPTION (provided by applicant): Obesity has become an epidemic disease and a major risk factor for the development of insulin resistance and type 2 diabetes. Two types of adipose tissues exist in humans and rodents. White adipose tissue (WAT) is essential for maintaining whole body energy homeostasis by storing excessive energy when nutrients are in surplus and releasing free fatty acids as fuels during energy shortage. Pathological expansion of WAT is the basis for obesity development. WAT derived inflammatory events characterized by macrophage infiltration in obese state are considered as a causal factor for the development of obesity-related insulin resistance. In contrast, brown adipose tissue (BAT) is a thermogenic organ and can dissipate energy as heat and enhanced BAT function is desired for treating obesity. In this proposal, sucrose non-fermenting related kinase (SNRK) has been identified as a potential suppressor of WAT inflammation in response to over-nutrition as well as a critical factor for BAT development and adaptive thermogenesis. Our studies demonstrate that SNRK is most abundantly expressed in WAT and BAT, and the expression levels as well as activities are significantly decreased in both tissues in obese mice. Global SNRK deficiency is perinatal lethal and pups can only survive for 1 day. Reduction of SNRK expression induces inflammation in cultured white adipocytes, in WAT of global SNRK heterozygous mice and in WAT of adipose specific SNRK knockout mice. In BAT, SNRK expression can be induced by cold exposure and leptin treatment. SNRK deficiency significantly reduces expression of PRDM16 and UCP1 in BAT of new born pups, impairs mitochondria morphology, and significantly reduces oxygen consumption of primary brown adipocytes. We hypothesize that SNRK is a critical regulator to integrate nutrient input and metabolism, and SNRK deficiency will lead to WAT inflammation and impairment of BAT function. The following aims will be pursued: 1) Investigate the role of SNRK in WAT development and inflammation; 2) Determine the effect of inducible SNRK deficiency on WAT inflammation of adult mice; 3) Dissect the role of SNRK in BAT development and function. The main method is to use loss-of-function adipose tissue specific, inducible adipose tissue specific and BAT specific SNRK knockout mouse models. If the proposed goals are accomplished, the results will provide novel information to understand the molecular mechanism of obesity-related metabolic disorders and shed light on potential new therapeutic direction.

 描述（由申请人提供）：肥胖已成为一种流行病，是胰岛素抵抗和2型糖尿病发展的主要危险因素。两种类型的脂肪组织存在于人类和啮齿动物中。白色脂肪组织（WAT）是维持全身能量平衡所必需的，其在营养过剩时储存过量的能量，在能量不足时释放游离脂肪酸作为燃料。WAT的病理性扩张是肥胖发展的基础。肥胖状态下以巨噬细胞浸润为特征的WAT衍生的炎症事件被认为是肥胖相关胰岛素抵抗发展的因果因素。相比之下，棕色脂肪组织（BAT）是产热器官，并且可以将能量耗散为热量，并且期望增强的BAT功能用于治疗肥胖。在该提议中，蔗糖非发酵相关激酶（SNRK）已被鉴定为响应于营养过剩的WAT炎症的潜在抑制剂，以及BAT发育和适应性产热的关键因素。我们的研究表明，SNRK在WAT和BAT中表达最丰富，并且在肥胖小鼠的两种组织中表达水平和活性显著降低。全球SNRK缺乏症是围产期致死性的，幼崽只能存活1天。在培养的白色脂肪细胞中、在整体SNRK杂合小鼠的WAT中和在脂肪特异性SNRK敲除小鼠的WAT中，SNRK表达的减少诱导炎症。在BAT中，SNRK的表达可以通过冷暴露和瘦素处理来诱导。SNRK缺乏显著降低新生幼崽BAT中PRDM 16和UCP 1的表达，损害线粒体形态，并显著降低原代棕色脂肪细胞的耗氧量。我们假设SNRK是整合营养输入和代谢的关键调节因子，SNRK缺乏将导致WAT炎症和BAT功能受损。本研究的目的是：1）研究SNRK在WAT发育和炎症中的作用; 2）确定诱导型SNRK缺陷对成年小鼠WAT炎症的影响; 3）分析SNRK在BAT发育和功能中的作用。主要的方法是采用功能缺失型脂肪组织特异性、诱导型脂肪组织特异性和BAT特异性SNRK基因敲除小鼠模型。如果实现了上述目标，这些结果将为了解肥胖相关代谢紊乱的分子机制提供新的信息，并为潜在的新治疗方向提供线索。