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Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis
Open accessAbstract
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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“Also, the unique enrichment of genes involved in calcium transport and ossification in hypertrophic Ad4 adipocytes may account for the frequent occurrence of calcium deposits observed in obese adipocytes (Giordano et al., 2013).”
From Robust single-nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity (2025) · cites this paper as Giordano et al., 2013
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El-Fattah, E. E. A., Ngai, G., Mooney, R., & Aboody, K. S. (2026) · Current Obesity Reports · doi:10.1007/s13679-026-00750-3
Suganami, T., Tanaka, M., & Itoh, M. (2026) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2026.109123
Vezzani, B., Tamburini, E., Terenziani, A., Oliverio, N. I., Croci, S., & Bartolomucci, A. (2026) · Adipocyte · doi:10.1080/21623945.2026.2736340
Klemm, D. (2024) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.10835022
Metadata
- Authors
- Giordano, A., Murano, I., Mondini, E., Perugini, J., Smorlesi, A., Severi, I., Barazzoni, R., Scherer, P. E., & Cinti, S.
- Affiliations
- University of Trieste (IT)
- The University of Texas Southwestern Medical Center (US)
- Marche Polytechnic University (IT)
- Corresponding author
- Cinti, Saverio
- ORCID
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 54
- Issue
- 9
- Pages
- 2423-2436
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC3735940
- OpenAlex
- W1968144622
- Cited by
- 297
- References
- 52
- Citations by year
- 2026: 17 · 2025: 18 · 2024: 25 · 2023: 32 · 2022: 38 · 2021: 27 · 2020: 31 · 2019: 18 · 2018: 20 · 2017: 20 · 2016: 12 · 2015: 19 · 2014: 15 · 2013: 4
- FWCI
- 12.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Funders
- European Commission (278373)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- obesity, pyroptosis, NLRP3 inflammasome, caspase-1, white adipose tissue inflammation, crown-like structures, leptin deficiency, db/db mice, ob/ob mice, oxidative stress, reactive oxygen species, calcium accumulation, cholesterol crystals, adipocyte ultrastructure, visceral adipose tissue, subcutaneous adipose tissue, programmed cell death
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Female, Obesity, Ultrasonography, Cell Death, Adipocytes, Oxidative Stress, Leptin, Subcutaneous Fat, Intra-Abdominal Fat, Mice, Receptors, Leptin, Inflammasomes, Diet, High-Fat
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