Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis

• Published in: Journal of lipid research 2013-09, Vol.54 (9), p.2423-2436
• Main Authors: Giordano, Antonio, Murano, Incoronata, Mondini, Eleonora, Perugini, Jessica, Smorlesi, Arianna, Severi, Ilenia, Barazzoni, Rocco, Scherer, Philipp E., Cinti, Saverio
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; Adipocytes - pathology; Adipocytes - ultrastructure; adipose tissue; Animals; Carrier Proteins - metabolism; Cell Death; diabetes; Diet, High-Fat - adverse effects; electron microscopy; Female; Inflammasomes - metabolism; inflammation; Intra-Abdominal Fat - pathology; Leptin - deficiency; Leptin - genetics; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; obesity; Obesity - diagnostic imaging; Obesity - etiology; Obesity - metabolism; Obesity - pathology; Oxidative Stress; Receptors, Leptin - deficiency; Receptors, Leptin - genetics; Subcutaneous Fat - pathology; Ultrasonography
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M038638

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.