Lack of adipose tissue lipolysis protects against pressure overload-induced heart failure

Abstract Prognosis of severe heart failure is unacceptably high, and it is our urgent task to find therapies for this critical condition. It has been reported that low body temperature predicts poor clinical outcomes in patients with heart failure, however, underlying mechanisms and pathological implications are largely unknown. Brown adipose tissue (BAT) was initially characterized as a heat generating organ, and studies suggest that BAT has crucial roles for the maintenance of systemic metabolic health. Here we show that BAT dysfunction develops in a murine thoracic aortic constriction (TAC) model, and has a causal role for promoting pathologies in failing heart. TAC operation led to a significant reduction both in intraperitoneal and subcutaneous temperature. TUNEL-positive cells significantly increased in BAT during left ventricular (LV)-pressure overload, and in-vitro studies with differentiated brown adipocytes suggested that the chronic activation of adrenergic signaling promotes apoptosis in these cells. Gain of BAT function model, generated with BAT implantation into peritoneal cavity, improved thermogenesis and ameliorated cardiac dysfunction in TAC. In contrast, genetic model of BAT dysfunction promoted cardiac dysfunction. Metabolomic analyses showed that BAT dysfunction led to an increase of oxidized choline that promoted metabolic dysfunction in the failing heart. Electron microscope study showed that oxidized choline induced mitochondrial dysfunction in vitro as well as in vivo settings. Extracellular flux analyzerindicated that oxidized choline suppresses oxidative phosphorylation in mitochondria. We found that dilated cardiomyopathy patients have lower body temperature, and confirmed by metabolomic study that both choline and oxidized choline are increased in circulation. Maintenance of BAT homeostasis and suppression of oxidized choline would become a novel therapeutic target for heart failure.

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Abstract 213: Fat Tissue specific Adipose Triglyceride Lipase as a major determinant for the development of pressure overload-induced heart failure

Hypertension ◽

10.1161/hyp.64.suppl_1.213 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Janek Salatzki ◽

Sarah Brix ◽

Zsofia Ban ◽

Daniela Fliegner ◽

Verena Benz ◽

...

Keyword(s):

Heart Failure ◽

Adipose Tissue ◽

Fatty Acid ◽

Cardiac Hypertrophy ◽

Left Ventricular Mass ◽

Pressure Overload ◽

Tolerance Test ◽

Left Ventricular ◽

Adipose Triglyceride Lipase ◽

Triglyceride Lipase

Introduction: Myocardial metabolism undergoes change in response to pathological cardiac hypertrophy (PH), characterized by increased reliance on glucose oxidation, decreased free fatty acid (FFA) oxidation and a loss of metabolic flexibility. Cardiac metabolism is influenced by other organs such as adipose tissue. Hence, we aimed to investigate the effect of Adipose Triglyceride Lipase (ATGL) in adipose tissue on the development of PH and heart failure (HF) in a pressure overload-induced cardiac hypertrophy model in mice. Methods: Male adipose tissue specific ATGL-knock out (atATGL-KO) and wild type mice (WT) underwent sham surgery (sham) or transverse aortic constriction (TAC). After 11 weeks, mice were sacrificed and organs were harvested. We performed echocardiography one week before and 11 weeks after surgery. Left ventricular mass (LVM), left ventricular mass/tibia length (LVM/TL) and ejection fraction (EF) were calculated. Beta-myosin heavy chain (β-MyHC) was measured in RNA of hearts. Insulin resistance was assessed by an intraperitoneal glucose tolerance test (GTT) and an insulin tolerance test (ITT). FFAs were measured in serum in total. Results: LVM and LVM/TL in WT was significantly higher compared to atATGL-KO after TAC (LVM/TL [mg/mm] WT-TAC: 18,0±2,2; atATGL-KO-TAC: 13,1±2,3; p<0,01). The higher increase of LVM in WT was associated with a larger left ventricle internal diameter. Reduction of EF was significantly more pronounced in WT compared to atATGL-KO ([%] WT: 28,81±6,9 atATGL-KO: 42,39±4,5; p<0,01). Beta-MyHC, a marker for PH, was markedly higher in WT-TAC than in atATGL-KO-TAC (WT-TAC: 11,3±3,6; atATGL-KO-TAC: 1.9±0,6; p<0,01). While WT-TAC showed higher Serum FFA-levels than atATGL-KO-TAC ([mmol/l] WT-TAC: 0,97±0,086; atATGL-KO-TAC: 0,49±0,032; p<0,001), GTT and ITT revealed a higher insulin sensitivity in atATGL-KO-TAC compared to WT-TAC. Conclusion: The present study demonstrates that atATGL is a crucial determinant for the development of pressure overload-induced PH and HI. The lack of ATGL in adipose tissue, the associated reduction of fatty acid release in the circulation and subsequent switches in cardiac energy substrates from free fatty acids to glucose are potential underlying mechanisms of this process.

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Abstract 118: Adipose Inflammation Is Critically Involved in the Progression of Heart Failure During Pressure Overload

Circulation Research ◽

10.1161/res.111.suppl_1.a118 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Ippei Shimizu ◽

Tohru Minamino ◽

Yohko Yoshida ◽

Taro Katsuno ◽

Issei Komuro ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Adipose Tissue ◽

Cardiac Function ◽

Systolic Dysfunction ◽

Pressure Overload ◽

Chronic Phase ◽

Metabolic Abnormalities ◽

Underlying Mechanisms ◽

Adipose Inflammation

Several clinical studies have shown that insulin resistance is prevalent among patients with impaired cardiac function and that systemic insulin resistance is the risk factor for the development of heart failure; however, underlying mechanisms have not been fully elucidated. We have previously reported that increased p53 level in adipose tissue is crucially involved in adipose inflammation and insulin resistance during pressure overload. Here we show that . Pressure overload increased sympathetic activity and promoted lipolysis in adipose tissue. Accelerated lipolysis resulted in increases of reactive oxygen species and DNA damage, leading to up-regulation of adipose p53. This up-regulation activated the NF-kappaB pathway and induced adipose inflammation and insulin resistance. Genetic disruption of adipose p53 markedly attenuated adipose inflammation and metabolic abnormalities associated with heart failure. We also observed that cardiac function and survival in the chronic phase of heart failure were significantly better in adipose tissue p53-deficient mice than control littermates. Pharmacological inhibition of adipose p53 after imposing pressure overload also improved cardiac dysfunction as well as insulin resistance in the chronic phase of heart failure. These results suggest that inhibition of adipose inflammation is a potential target for treating metabolic abnormalities and systolic dysfunction in patients with heart failure.

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