Dataset Information

A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function.

ABSTRACT:

Background

Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function.

Methods

To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1^-/-) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease.

Results

Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1^-/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease.

Conclusions

Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.

SUBMITTER: Pinckard KM

PROVIDER: S-EPMC7856257 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcute myocardial infarction (AMI) is the most prevalent cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). However, strict blood glucose control does not always prevent the development and progression of AMI. Therefore, the present study aimed to explore potential new biomarkers associated with the occurrence of AMI in T2DM patients.MethodsA total of 82 participants were recruited, including the control group (n = 28), T2DM without AMI group (T2DM, n = 30) and T2DM with initial AMI group (T2DM + AMI, n = 24). The untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS) analysis was performed to evaluate the changes in serum metabolites. Then, candidate metabolites were determined using ELISA method in the validation study (n = 126/T2DM group, n = 122/T2DM + AMI group).ResultsThe results showed that 146 differential serum metabolites were identified among the control, T2DM and T2DM + AMI, Moreover, 16 differentially-expressed metabolites were significantly altered in T2DM + AMI compared to T2DM. Amino acid and lipid pathways were the major involved pathways. Furthermore, three candidate differential metabolites, 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), noradrenaline (NE) and estrone sulfate (ES), were selected for validation study. Serum levels of 12,13-diHOME and NE in T2DM + AMI were significantly higher than those in T2DM. Multivariate logistic analyses showed that 12,13-diHOME (OR, 1.491; 95% CI 1.230-1.807, P < 0.001) and NE (OR, 8.636; 95% CI 2.303-32.392, P = 0.001) were independent risk factors for AMI occurrence in T2T2DM patients. The area under receiver operating characteristic (ROC) curve (AUC) were 0.757 (95% CI 0.697-0.817, P < 0.001) and 0.711(95% CI 0.648-0.775, P < 0.001), respectively. The combination of both significantly improved the AUC to 0.816 (95% CI 0.763-0.869, P < 0.001).Conclusions12,13-diHOME and NE may lead to understanding the possible metabolic alterations associated with AMI onset in T2DM population and serve as promising risk factors and therapeutic targets.

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