title: Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis.
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.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Ancona, Ancona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Incoronata
authors.initials: I
authors.lastname: Murano
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mondini
authors.forename: Jessica
authors.initials: J
authors.lastname: Perugini
authors.forename: Arianna
authors.initials: A
authors.lastname: Smorlesi
authors.forename: Ilenia
authors.initials: I
authors.lastname: Severi
authors.forename: Rocco
authors.initials: R
authors.lastname: Barazzoni
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D058847:Inflammasomes / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000473:pathology; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D050151:Subcutaneous Fat / Q000473:pathology; D014463:Ultrasonography
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020738:Leptin; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D054411:Receptors, Leptin
keywords: adipose tissue; diabetes; electron microscopy; inflammation; obesity