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.

项目概要： 心力衰竭的发病机制与全身代谢功能障碍有关，这种合并症可能涉及 外周器官，并导致糖尿病患者和非糖尿病患者的胰岛素抵抗。 脂肪组织对心脏病理应激的相互反应，并将研究如何 脂肪组织活动影响心脏代谢重塑。 我们的每个 MPI 实验室都发现了脂肪组织可塑性的短暂变化。 失代偿性心脏肥大的发病机制仅响应于病理应激，没有任何 主要代谢压力，例如糖尿病、营养过剩或肥胖。这一发现和我们未发表的数据。 暗示心利钠肽 (NP) 作为脂肪活化的介质，并表明 NP 是被诱导的 即使没有病理应激，也能减少心脏对长链脂肪酸 (LCFA) 的氧化。 初步数据揭示了白色（WAT）和棕色（BAT）的一系列深刻的、性别特异性的早期反应 脂肪组织活动导致心脏压力超负荷，包括 WAT 的开始和脂解的诱导 而心脏对病理应激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谱的影响 病理性肥大的发展实际上尚未被探索过，因此，我们认为：1） 病理应激期间心脏中脂肪酸氧化减少的代谢反应诱导可塑性 WAT 由心脏 NP 以性别特异性方式介导，与 β-肾上腺素能刺激不同， 对葡萄糖耐量的下游影响；2) WAT 的持续开始和 BAT 的激活赋予 预防不良心脏代谢重塑的心脏保护 该研究设计支持三个特定的目标。 目的： 1. 阐明脂肪细胞肾上腺素能激活对 WAT 开始的影响以及心脏 LCFA 的反应 TAC期间代谢与脂肪肾上腺素能的激活和抑制2.确定是否脂肪； 可塑性源自对 TAC 直接反应的 NP 效应或减少的 LCFA 的代谢转变 3. 研究脂肪褐变对雄性和雌性小鼠的潜在心脏保护作用 衰竭心脏的血脂谱总体目标是：1) 确定相互的代谢反应。 通过心脏 NP 产生和脂肪因子/脂因子在病理应激的心脏和脂肪组织之间建立联系 分别释放（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 开始或的潜力； BAT 激活通过代谢信号提供心脏保护作用，这些发现将为我们提供新的见解。 发病机制中脂肪反应及其对心脏代谢重塑的贡献 失代偿性心脏肥大，有可能确定补救进展的目标 明显的心力衰竭并改善外周和全身代谢功能障碍。