Adipose tissue mediates cardiac metabolic remodeling in the pathologically stressed heart in the absence of primary metabolic stress

在没有主要代谢应激的情况下，脂肪组织介导病理应激心脏的心脏代谢重塑

• 批准号: 10657015
• 负责人: E DOUGLAS LEWANDOWSKI
• 金额: $ 78.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657015
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Aortic Valve Stenosis; Blood Vessels; Brown Fat; Cardiac; Carnitine Palmitoyltransferase I; Catecholamines; Characteristics; Data; Development; Diabetes Mellitus; EFRAC; Enzymes; Fatty acid glycerol esters; Female; Genes; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; Insulin Resistance; Laboratories; Link; Lipids; Lipolysis; Liver; Mediating; Mediator; Metabolic; Metabolic dysfunction; Metabolic stress; Metabolism; Mitochondria; Modeling; Mus; Myocardial tissue; Myocardium; Myosin Heavy Chains; Natriuretic Peptides; Nutrient; Obesity; Organ; Outcome; Pathogenesis; Pathologic; Patients; Peripheral; Phase; Phenotype; Production; Protein Isoforms; Publishing; Rattus; Receptor Activation; Receptors, Adrenergic, beta-3; Research; Research Design; Role; Sex Differences; Signal Transduction; Source; Stress; Testing; Thermogenesis; Tissue Transplantation; adipokines; antagonist; aorta constriction; cardioprotection; comorbidity; event cycle; fatty acid metabolism; fatty acid oxidation; glucose tolerance; heart metabolism; improved; insight; insulin sensitivity; interest; knock-down; lipid metabolism; long chain fatty acid; male; mouse model; natural hypothermia; novel; overexpression; oxidation; preservation; pressure; remediation; response; sex; stem; subcutaneous; uncoupling protein 1; uptake; virtual

Project Summary: The pathogenesis of heart failure is linked to systemic metabolic dysfunction, a comorbidity likely involving peripheral organs, and resulting in insulin resistance in patients with and without diabetes. This study focuses on the reciprocal response of adipose tissue to pathological stress on the heart and will investigate how adipose tissue activity affects cardiac metabolic remodeling. This proposal originates from novel findings by each of the MPI laboratories. We have identified transient changes in adipose tissue plasticity during the pathogenesis of decompensated cardiac hypertrophy in response to pathological stress alone, absent any primary metabolic stress, such as diabetes, nutrient overload, or obesity. This finding and our unpublished data implicate cardiac natriuretic peptides (NP) as mediators of adipose activation and show that NPs are induced by a reduction in long chain fatty acid (LCFA) oxidation by the heart, even without pathological stress. Preliminary data reveal a profound, sex-specific array of early responses in white (WAT) and brown (BAT) adipose tissue activity to cardiac pressure overload that include beiging of WAT and induction of a lipolytic phenotype with cold exposure. While the cardiac responses to pathological stress include maladaptive remodeling of lipid metabolism, the effects of adipose plasticity on the cardiac lipid profile during the development of pathological hypertrophy are virtually unexplored. Thus, we hypothesize that: 1) the metabolic response of reduced fatty acid oxidation in the heart during pathological stress induces plasticity of WAT that is mediated by cardiac NPs in a sex-specific manner, distinct from β-adrenergic stimulation, with downstream effects on glucose tolerance; and 2) sustained beiging of WAT and activation of BAT confer cardioprotection against adverse cardiac metabolic remodeling. The research design supports three specific aims: 1. Elucidate effects of adipocyte adrenergic activation on WAT beiging, and responses of cardiac LCFA metabolism during TAC with adipose adrenergic activation and inhibition; 2. Determine whether adipose plasticity results from NP effects in direct response to TAC or from the metabolic shift of reduced LCFA oxidation in male and female mice; 3. Investigate a potential cardioprotective role of adipose browning on the lipid profile of failing hearts. The overall objectives are to: 1) determine the reciprocal metabolic responses between the pathologically stressed heart and adipose tissue via cardiac NP production and adipokine/lipokine release (namely 12,13-diHOME), respectively; 2) elucidate the consequences of sex differences in the responses of adipose tissue and myocardium to cardiac stress; and 3) explore the potential for WAT beiging or BAT activation to provide cardioprotection via metabolic signaling. The findings will contribute new insights into the adipose responses and contributions to metabolic remodeling of the heart during the pathogenesis of decompensated cardiac hypertrophy, with the potential to identify targets for remediating the progression to overt heart failure and improving peripheral and systemic metabolic dysfunction.

项目摘要： 心力衰竭的发病机理与系统性代谢功能障碍有关，合并症可能涉及 外围器官，并在患有和患有糖尿病患者的患者中导致胰岛素抵抗。这项研究重点 关于脂肪组织对心脏病理压力的相​​互反应，并将研究如何 脂肪组织活性会影响心脏代谢重塑。该提议源自新颖的发现 每个MPI实验室。我们已经确定了脂肪组织可塑性的短暂变化 单独响应病理胁迫的反应型心脏肥大的发病机理，没有任何 原发性代谢应激，例如糖尿病，营养超负荷或肥胖。这一发现和我们未发表的数据 实施心发脂性胡椒（NP）作为脂肪激活的介体，并表明NP是诱导的 通过减少长链脂肪酸（LCFA）的氧化，即使没有病理应激。 初步数据揭示了白色（WAT）和棕色（BAT）的深刻，性别特定的早期反应 脂肪组织活性对心脏压力超负荷，包括成为WAT和脂肪溶液的诱导 与冷暴露的表型。而心脏对病理压力的反应包括适应不良 脂质代谢的重塑，脂肪可塑性对心脏脂质剖面的影响 病理肥大的发展几乎是意外的。那就是我们假设：1） 病理应激期间脂肪酸氧化减少的代谢反应诱导 由心脏NP以性别特异性介导的WAT，与β-肾上腺素模拟不同，与 下游对葡萄糖耐受的影响； 2）持续成为WAT和激活蝙蝠会议 针对不良心脏代谢重塑的心脏保护。研究设计支持三个特定的 目的：1。阐明脂肪细胞肾上腺素激活对WAT的影响以及心脏LCFA的反应 脂肪肾上腺素肾上腺素激活和抑制作用期间的代谢； 2。确定是否脂肪 可塑性是由NP效应直接响应TAC或降低LCFA的代谢转移而产生的 雄性和雌性小鼠的氧化； 3。研究脂肪褐变对脂肪的潜在心脏保护作用 失败心脏的脂质曲线。总体目标是：1）确定倒代谢反应 通过心脏NP产生的病理压力心脏和脂肪组织之间 释放（即12,13-dihome）； 2）阐明性别差异的后果 脂肪组织和心肌对心脏应激的反应； 3）探索wat的潜力或 BAT激活以通过代谢信号传导提供心脏保护。这些发现将为新见解 脂肪反应和对心脏代谢重塑的贡献 代偿性心脏肥大，具有识别靶标的靶标的 明显的心力衰竭以及改善周围和全身代谢功能障碍。