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

项目总结： 心力衰竭的发病机制与全身代谢功能障碍有关，这种共病可能涉及 外周器官，并导致胰岛素抵抗的患者和非糖尿病患者。这项研究的重点是 关于脂肪组织对心脏病理性应激的相互反应，并将研究如何 脂肪组织活动影响心脏代谢重塑。这一建议源于由 每个MPI实验室。我们已经确定了脂肪组织可塑性的瞬时变化 仅对病理性应激反应的失代偿性心肌肥厚的发病机制 原发代谢应激，如糖尿病、营养过载或肥胖。这一发现和我们未公布的数据 将心钠素(NP)作为脂肪激活的介质，并表明NPs是被诱导的 通过减少心脏对长链脂肪酸(LCFA)的氧化，即使在没有病理性应激的情况下。 初步数据显示，白色(Wat)和棕色(BAT)的早期反应具有深刻的性别差异 脂肪组织对心脏压力超负荷的活性，包括褐变的水和诱导脂解 有冷暴露的表型。而心脏对病理性应激的反应包括适应不良 脂代谢重塑，脂肪可塑性对心脏脂质代谢的影响 病理性肥大的发展几乎是未知的。因此，我们假设：1) 病理性应激期间心脏减少脂肪酸氧化的代谢反应诱导血管可塑性 WAT是由心脏NPs以性别特异性的方式介导的，不同于β肾上腺素能刺激， 下游对糖耐量的影响；以及2)Wat的持续褐变和BAT授予的激活 对不良心脏代谢重构的心脏保护作用。研究设计支持三个具体的 目的：1.阐明脂肪细胞肾上腺素能激活对水环境和心脏LCFA反应的影响 TAC中的代谢与脂肪肾上腺素能的激活和抑制；2.确定脂肪是否 可塑性是由于对TAC的直接反应中的NP效应或减少的LCFA的代谢变化造成的 雄性和雌性小鼠的氧化；3.研究脂肪褐变对小鼠心脏的潜在保护作用 心力衰竭患者的血脂谱。总体目标是：1)确定相互的代谢反应 病理应激心脏和脂肪组织之间通过心脏NP的产生和脂肪因子/脂肪因子之间的关系 分别释放(即12，13-diHOME)；2)阐明性别差异在 脂肪组织和心肌对心脏应激的反应；以及3)探索Wat Beiging or BAT激活，通过代谢信号提供心脏保护。这些发现将有助于对 高血压性心脏病发病过程中脂肪反应及对心脏代谢重塑的影响 失代偿性心肌肥厚，有可能确定治疗进展到 明显的心力衰竭和改善外周和全身代谢功能障碍。

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 This finding and our unpublished data implicate cardiac natriuretic peptides (NP) as mediators of adipose activation and show that NPs are induced by a reduction in long chain fatty acid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.