A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function
Open accessAbstract
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.
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A sustained increase in plasma 12,13-diHOME preserves cardiac function and remodelling and increases cardiac haemodynamics through a direct cardiomyocyte effect.
“These findings suggest that a sustained increase in plasma levels of 12,13-diHOME preserves cardiac function and remodelling and increases cardiac haemodynamics through a direct effect on the cardiomyocyte.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [93]
In humans, the presence of cardiovascular disease is associated with decreased plasma 12,13-diHOME.
“in whom the presence of cardiovascular disease is associated with decreased plasma levels of 12,13-diHOME93.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [93]
BAT transplantation in mice increased plasma 12,13-diHOME and improved cardiac haemodynamics.
“A 2021 study showed that BAT transplantation in mice increased plasma levels of 12,13-diHOME and improved cardiac haemodynamics93.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [93]
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- Authors
- Pinckard, K. M., Shettigar, V. K., Wright, K. R., Abay, E., Baer, L. A., Vidal, P., Dewal, R. S., Das, D., Duarte-Sanmiguel, S., Hernández-Saavedra, D., Arts, P. J., Lehnig, A. C., Bussberg, V., Narain, N. R., Kiebish, M. A., Yi, F., Sparks, L. M., Goodpaster, B. H., Smith, S. R., Pratley, R. E., Lewandowski, E. D., Raman, S. V., Wold, L. E., Gallego-Perez, D., Coen, P. M., Ziolo, M. T., & Stanford, K. I.
- Affiliations
- The Ohio State University Wexner Medical Center (US)
- The Ohio State University (US)
- Department of Biomedical Engineering (D.D., S.D.-S., D.G.P.), The Ohio State University, Columbus.
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (K.M.P., V.K.S., K.R.W., E.A., L.A.B., P.V., R.S.D., D.H.-S., P.J.A., A.C.L., E.D.L., S.V.R., L.E.W., D.G.P., M.T.Z., K.I.S.).
- Berg (United States) (US)
- AdventHealth Orlando (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Ziolo, Mark T.
- Stanford, Kristin I.
- ORCID
- Shettigar, Vikram K.
- Abay, Eaman
- Vidal, Pablo
- Dewal, Revati S.
- Das, Devleena
- Hernández-Saavedra, Diego
- Arts, Peter J.
- Lehnig, Adam C.
- Bussberg, Valerie
- Narain, Niven R.
- Kiebish, Michael A.
- Sparks, Lauren M.
- Goodpaster, Bret H.
- Smith, Steven R.
- Pratley, Richard E.
- Lewandowski, E. Douglas
- Raman, Subha V.
- Wold, Loren E.
- Gallego-Perez, Daniel
- Coen, Paul M.
- Ziolo, Mark T.
- Stanford, Kristin I.
- Venue
- Circulation
- Published
- 2021-01-12
- Volume
- 143
- Issue
- 2
- Pages
- 145-159
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC7856257
- OpenAlex
- W3094633340
- Cited by
- 157
- References
- 52
- Citations by year
- 2026: 23 · 2025: 26 · 2024: 32 · 2023: 31 · 2022: 30 · 2021: 13 · 2020: 1
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (17CSA33610078-STANFORD)
- National Institute on Aging (R01AG060542)
- National Heart, Lung, and Blood Institute (R01HL138738, T32HL134616)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP1DK126199)
- National Institute of Biomedical Imaging and Bioengineering (DP2EB028110)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- brown adipose tissue, 12,13-diHOME, lipokines, cardiac function, mitochondrial respiration, high-fat diet, cardiac remodeling, heart disease
- MeSH terms
- Lipidomics, Aged, Animals, Adipose Tissue, Brown, Cells, Cultured, Female, Heart Failure, Humans, Male, Mice, Inbred C57BL, Middle Aged, Oleic Acids, Physical Conditioning, Animal, Cohort Studies, Mice
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