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A cycle of inflammatory adipocyte death and regeneration in murine adipose tissue

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posted on 18.01.2022, 13:02 by Ada AdminAda Admin, Akio Monji, Yang Zhang, G.V. Naveen Kumar, Christelle Guillermier, Soomin Kim, Benjamin Olenchock, Matthew L. Steinhauser
Adipose tissue (AT) expands by a combination of two fundamental cellular mechanisms: hypertrophic growth of existing adipocytes or through generation of new adipocytes also known as hyperplastic growth. Multiple lines of evidence suggest a limited capacity for hyperplastic growth of adipose tissue in adulthood and that adipocyte number is relatively stable even with fluctuations in AT mass. If adipocyte number is stable in adulthood, despite well-documented birth and death of adipocytes, then this would suggest that birth may be coupled to death in a regenerative cycle. To test this hypothesis, we examined the dynamics of birth of new fat cells in relationship to adipocyte death, using high fidelity stable isotope tracer methods in C57Bl6 mice. We discovered birth of new adipocytes at higher frequency in histological proximity to dead adipocytes. In diet-induced obesity, adipogenesis surged after an adipocyte death peak beyond 8 weeks of high fat feeding. Through transcriptional analyses of adipose tissue and fractionated adipocytes, we found that the dominant cell death signals were inflammasome-related. Pro-inflammatory signals were particularly evident in hypertrophied adipocytes or with deletion of a constitutive oxygen sensor and inhibitor of Hypoxia inducible factor (HIF), Egln1. We leveraged the potential role for the inflammasome in adipocyte death to test the adipocyte death-birth hypothesis, finding that Caspase 1 loss of function attenuated adipocyte death and birth in murine visceral adipose tissue. These data collectively point to a regenerative cycle of adipocyte death and birth as a driver of adipogenesis in adult murine adipose tissue.

Funding

U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Diabetes and Digestive and Kidney Diseases K08DK090147 R01DK120659 R03DK106477

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