Journal of Lipid Research
Volume 54, Issue 9, September 2013, Pages 2423-2436
Journal home page for Journal of Lipid Research

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

https://doi.org/10.1194/jlr.M038638Get rights and content
Under a Creative Commons license
open access

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.

adipose tissue
diabetes
obesity
electron microscopy
inflammation

Cited by (0)

This work was supported by grants from Marche Polytechnic University (Contributi Ricerca Scientifica), the European Commission's Seventh Framework Programme for Research and Technological Development (EU FP7) project DIABAT (HEALTH-F2-2011-278373), and the Italian Ministry of University (PRIN 2010-11 to S.C.).

    Abbreviations

    CLS

    crown-like structure

    FAT-ATTAC

    fat apoptosis through targeted activation of caspase-8

    HFD

    high-fat diet

    HOMA

    Homeostasis Model Assessment

    HR-SEM

    high-resolution scanning electron microscopy

    IL

    interleukin

    NLRP3

    nucleotide-binding oligomerization domain (NOD)-like receptor (NLR)-3

    RER

    rough endoplasmic reticulum

    ROS

    reactive oxygen species

    TEM

    transmission electron microscopy

    TRXNIP

    thioredoxin-interacting protein

    WAT

    white adipose tissue

    WT

    wild-type