Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis |
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Authors: | Antonio Giordano Incoronata Murano Eleonora Mondini Jessica Perugini Arianna Smorlesi Ilenia Severi Rocco Barazzoni Philipp E. Scherer Saverio Cinti |
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Affiliation: | *Department of Experimental and Clinical Medicine and;**Center of Obesity University of Ancona (Politecnica delle Marche)-United Hospitals, Ancona, Italy;†Department of Medical, Surgical and Health Sciences, University of Trieste,, Trieste, Italy; and;§Touchstone Diabetes Center, Department of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX |
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Abstract: | We previously suggested that, in obese animals and humans, white adipose tissue inflammation results from the death of hypertrophic adipocytes; these are then cleared by macrophages, giving rise to distinctive structures we denominated crown-like structures. Here we present evidence that subcutaneous and visceral hypertrophic adipocytes of leptin-deficient (ob/ob and db/db) obese mice exhibit ultrastructural abnormalities (including calcium accumulation and cholesterol crystals), many of which are more common in hyperglycemic db/db versus normoglycemic ob/ob mice and in visceral versus subcutaneous depots. Degenerating adipocytes whose intracellular content disperses in the extracellular space were also noted in obese mice; in addition, increased anti-reactive oxygen species enzyme expression in obese fat pads, documented by RT-PCR and immunohistochemistry, suggests that ultrastructural changes are accompanied by oxidative stress. RT-PCR showed NLRP3 inflammasome activation in the fat pads of both leptin-deficient and high-fat diet obese mice, in which formation of active caspase-1 was documented by immunohistochemistry in the cytoplasm of several hypertrophic adipocytes. Notably, caspase-1 was not detected in FAT-ATTAC transgenic mice, where adipocytes die of apoptosis. Thus, white adipocyte overexpansion induces a stress state that ultimately leads to death. NLRP3-dependent caspase-1 activation in hypertrophic adipocytes likely induces obese adipocyte death by pyroptosis, a proinflammatory programmed cell death. |
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Keywords: | adipose tissue diabetes obesity electron microscopy inflammation |
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