Apoptosis of hematopoietic progenitor-derived adipose tissue-resident macrophages contributes to insulin resistance after myocardial infarction
- 22 July 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (553)
- https://doi.org/10.1126/scitranslmed.aaw0638
Abstract
Patients with insulin resistance have high risk of cardiovascular disease such as myocardial infarction (MI). However, it is not known whether MI can initiate or aggravate insulin resistance. We observed that patients with ST-elevation MI and mice with MI had de novo hyperglycemia and features of insulin resistance, respectively. In mouse models of both myocardial and skeletal muscle injury, we observed that the number of visceral adipose tissue (VAT)-resident macrophages decreased because of apoptosis after these distant organ injuries. Patients displayed a similar decrease in VAT-resident macrophage numbers and developed systemic insulin resistance after ST-elevation MI. Loss of VAT-resident macrophages after MI injury led to systemic insulin resistance in non-diabetic mice. Danger signaling-associated protein high mobility group box 1 was released by the dead myocardium after MI in rodents and triggered macrophage apoptosis via Toll-like receptor 4. The VAT-resident macrophage population in the steady state in mice was transcriptomically distinct from macrophages in the brain, skin, kidney, bone marrow, lungs, and liver and was derived from hematopoietic progenitor cells just after birth. Mechanistically, VAT-resident macrophage apoptosis and de novo insulin resistance in mouse models of MI were linked to diminished concentrations of macrophage colony-stimulating factor and adiponectin. Collectively, these findings demonstrate a previously unappreciated role of adipose tissue-resident macrophages in sensing remote organ injury and promoting MI pathogenesis.Funding Information
- National Institutes of Health (1R01HL143967)
- National Institutes of Health (R00HL12076)
- American Heart Association (20POST35210088)
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