Inflammation of adipose tissue (AT) has been recently accepted as a first step towards obesity-mediated insulin resistance. We could previously show that mice fed with high fat diet (HFD) develop systemic insulin resistance (IR) and glucose intolerance (GI) associated with CD4-positive T-lymphocyte infiltration into visceral AT. These T-lymphocytes, when enriched in AT, participate in the development of fat tissue inflammation and subsequent recruitment of proinflammatory macrophages. The aim of this work was to elucidate the action of the insulin sensitizing PPARgamma on T-lymphocyte infiltration during development of IR, and comparison of the PPARgamma-mediated anti-inflammatory effects of rosiglitazone and telmisartan in diet-induced obesity model (DIO-model) in mice.

Aims: Heart failure (HF) is characterized by an overactivation of β-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, β-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently, we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in mice. In this study, we investigated the cardioprotective effects of a new pharmacological inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-induced cardiac damage. Methods and results: Male 129/Sv mice received repeated injections of isoproterenol (ISO, 25 mg/kg BW) to induce cardiac damage. Five days prior to ISO application, oral Atglistatin (2 mmol/kg diet) or control treatment was started. Two and twelve days after the last ISO injection cardiac function was analysed by echocardiography. The myocardial deformation was evaluated using speckle-tracking-technique. Twelve days after the last ISO injection, echocardiographic analysis revealed a markedly impaired global longitudinal strain, which was significantly improved by the application of Atglistatin. No changes in ejection fraction were observed. Further studies included histological-, WB-, and RT-qPCR-based analysis of cardiac tissue, followed by cell culture experiments and mass spectrometry-based lipidome analysis. ISO application induced subendocardial fibrosis and a profound pro-apoptotic cardiac response, as demonstrated using an apoptosis-specific gene expression-array. Atglistatin treatment led to a dramatic reduction of these pro-fibrotic and pro-apoptotic processes. We then identified a specific set of fatty acids (FAs) liberated from adipocytes under ISO stimulation (palmitic acid, palmitoleic acid, and oleic acid), which induced pro-apoptotic effects in cardiomyocytes. Atglistatin significantly blocked this adipocytic FA secretion. Conclusion: This study demonstrates cardioprotective effects of Atglistatin in a mouse model of catecholamine-induced cardiac damage/dysfunction, involving anti-apoptotic and anti-fibrotic actions. Notably, beneficial cardioprotective effects of Atglistatin are likely mediated by non-cardiac actions, supporting the concept that pharmacological targeting of adipose tissue may provide an effective way to treat cardiac dysfunction.

The cross talk between adipose tissue and the heart has an increasing importance for cardiac function under physiological and pathological conditions. This study characterizes the role of fat body lipolysis for cardiac function in Drosophila melanogaster. Perturbation of the function of the key lipolytic enzyme, brummer (bmm), an ortholog of the mammalian ATGL (adipose triglyceride lipase) exclusively in the fly's fat body, protected the heart against starvation-induced dysfunction. We further provide evidence that this protection is caused by the preservation of glycerolipid stores, resulting in a starvation-resistant maintenance of energy supply and adequate cardiac ATP synthesis. Finally, we suggest that alterations of lipolysis are tightly coupled to lipogenic processes, participating in the preservation of lipid energy substrates during starvation. Thus, we identified the inhibition of adipose tissue lipolysis and subsequent energy preservation as a protective mechanism against cardiac dysfunction during catabolic stress.

Cardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population’s rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, autophagy inducer rapamycin has been described to exert cardioprotective effects, it remains to be shown whether these effects can be attributed to improved cardiomyocyte autophagy and contractility. In vivo hypertrophy was induced by transverse aortic constriction (TAC), with mice receiving daily rapamycin injections beginning six weeks after surgery for four weeks. Echocardiographic analysis demonstrated TAC-induced HF and protein analyses showed abundance of modified proteins in TAC-hearts after 10 weeks, both reduced by rapamycin. In vitro, cardiomyocyte hypertrophy was mimicked by endothelin 1 (ET-1) and autophagy manipulated by silencing Atg5 in neonatal cardiomyocytes. ET-1 and siAtg5 decreased Atg5–Atg12 and LC3-II, increased natriuretic peptides, and decreased amplitude and early phase of contraction in cardiomyocytes, the latter two evaluated using ImageJ macro Myocyter recently developed by us. ET-1 further decreased cell contractility in control but not in siAtg5 cells. In conclusion, ET-1 decreased autophagy and cardiomyocyte contractility, in line with siAtg5-treated cells and the results of TAC-mice demonstrating a crucial role for autophagy in cardiomyocyte contractility and cardiac performance.

Palmitoleic acid (C16:1n7) has been identified as a regulator of physiological cardiac hypertrophy. In the present study, we aimed to investigate the molecular pathways involved in C16:1n7 responses in primary murine cardiomyocytes (PCM) and a mouse model of isoproterenol (ISO)-induced cardiac damage. PCMs were stimulated with C16:1n7 or a vehicle. Afterwards, RNA sequencing was performed using an Illumina HiSeq sequencer. Confirmatory analysis was performed in PCMs and HL-1 cardiomyocytes. For an in vivo study, 129 sv mice were orally treated with a vehicle or C16:1n7 for 22 days. After 5 days of pre-treatment, the mice were injected with ISO (25 mg/kg/d s. c.) for 4 consecutive days. Cardiac phenotyping was performed using echocardiography. In total, 129 genes were differentially expressed in PCMs stimulated with C16:1n7, including Angiopoietin-like factor 4 (Angptl4) and Pyruvate Dehydrogenase Kinase 4 (Pdk4). Both Angptl4 and Pdk4 are proxisome proliferator-activated receptor α/δ (PPARα/δ) target genes. Our in vivo results indicated cardioprotective and anti-fibrotic effects of C16:1n7 application in mice. This was associated with the C16:1n7-dependent regulation of the cardiac PPAR-specific signaling pathways. In conclusion, our experiments demonstrated that C16:1n7 might have protective effects on cardiac fibrosis and inflammation. Our study may help to develop future lipid-based therapies for catecholamine-induced cardiac damage.