Brown adipose tissue (BAT) is the primary non-shivering thermogenesis organ in mammals, which plays essential roles in maintaining the body temperature of infants. Although the development of BAT during embryogenesis has been well addressed in rodents, how BAT grows after birth remains unknown. Using mouse interscapular BAT (iBAT) as an example, we studied the cellular and molecular mechanisms that regulate postnatal BAT growth. By analyzing the developmental dynamics of brown adipocytes (BAs), we found that BAs size enlargement partially accounts for iBAT growth. By investigating the BAs cell cycle activities, we confirmed the presence of proliferative BAs in the neonatal mice. Two weeks after birth, most of the BAs exit cell cycle, and the further expansion of the BAT was mainly due to lipogenesis-mediated BAs volume increase. Microscopy and fluorescence-activated cell sorting analyses suggest that most BAs are mononuclear and diploid. Based on the developmental dynamics of brown adipocytes, we propose that the murine iBAT has two different growth phases between birth and weaning: increase of BAs size and number in the first two weeks, and BAs size enlargement thereafter. In summary, our data demonstrate that both lipogenesis and proliferation of BAs contribute to postnatal iBAT growth in mice.

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Cardiac injury is common in hospitalized COVID-19 patients and portends poorer prognosis and higher mortality. To better understand how SARS-CoV-2 (CoV-2) damages the heart, it is critical to elucidate the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. HCoV-NL63 is another human coronavirus with a Spike protein (NL63-S) that also engages ACE2 for virus entry but is known to only cause moderate respiratory symptoms. By comparing the pathological effects of NL63-S and CoV-2 spike protein (CoV-2-S), we tested the hypothesis that CoV-2-S damages the heart by activating cardiomyocyte (CM) innate immune responses, which is independent of ACE2.We found that CoV-2-S and not NL63-S interacted with Toll-like receptor 4 (TLR4), a crucial pattern recognition receptor responsible for detecting pathogen and initiating innate immune responses. Our data show that the S1 subunit of CoV-2-S (CoV-2-S1) interacts with the extracellular leucine-rich repeats-containing domain of TLR4 and activates NF-kB. To investigate the possible pathological role of CoV-2-S1 in the heart, we generated constructs that express membrane-localized CoV-2-S1 (S1-TM) or HCoV-NL63-S1 (NLS1-TM). AAV9-mediated, selective expression of the S1-TM and not NLS1-TM in CMs caused heart dysfunction, induced hypertrophic remodeling, and elicited cardiac inflammation. In vitro, overexpressing S1-TM in cultured neonatal rat ventricular CMs induced hypertrophy, decreased Myh6 and increased IL-6 . In the ventricular biopsy of a deceased patient with COVID-19 associated myocarditis, Spike protein and TLR4 were detected in both CMs and non-CMs, and these two proteins were absent in a healthy pre-pandemic human heart. In the ventricular biopsy of a patient who died of modified RNA vaccine-associated myocarditis, the expression of Spike protein was only detected in a small fraction of CMs, and no obvious TLR4 signal was detected in CMs. Because CoV-2-S does not interact with murine ACE2, our study presents a novel ACE2-independent pathological role of CoV-2-S. Additionally, our data suggest that modified RNA vaccine unlikely causes myocarditis by directly transfecting the CMs.

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