TY - JOUR
T1 - Time course of histomorphological changes in adipose tissue upon acute lipoatrophy
AU - Murano, I.
AU - Rutkowski, J. M.
AU - Wang, Q. A.
AU - Cho, Y. R.
AU - Scherer, P. E.
AU - Cinti, S.
N1 - Funding Information:
The research leading to these results has received funding from the European Community's 7th Framework Programme (FP7/2007-2013) under grant agreement no. 201608 ; from Fondazione Cariverona , Grant 2008 to S.C. and from COST ACTION BM0602 . PES was supported by NIH grants R01-DK55758 , R01-CA112023 , RC1-DK086629 and P01-DK088761 . JMR was supported by a postdoctoral fellowship from the NIH ( F32DK085935-01A1 ). QAW was supported by a postdoctoral fellowship from the ADA ( 7-11-MN-47 ).
PY - 2013/8
Y1 - 2013/8
N2 - Background and aims: Crown-like structures (CLS) are characteristic histopathology features of inflamed adipose tissues in obese mice and humans. In previous work, we suggested that these cells derived from macrophages primarily involved in the reabsorption of dead adipocytes. Here, we used a well-characterized transgenic mouse model in which the death of adipocytes in adult mice is inducible and highly synchronized. In this "FAT ATTAC" model, apoptosis is induced through forced dimerization of a caspase-8 fusion protein. Methods and results: 0, 0.5, 1, 2, 3 and 10 days post induction of adipocyte cell death, we analyzed mesenteric and epididymal adipose depots by histology, immunohistochemistry and electron microscopy. Upon induction of caspase-8 dimerization, numerous adipocytes lost immunoreactivity for perilipin, a marker for live adipocytes. In the same areas, we found adipocytes with hypertrophic mitochondria and signs of organelle degeneration. Neutrophils and lymphocytes were the main inflammatory cells present in the tissue, and the macrophages were predominantly Mac-2 negative. Over the course of ablation, Mac-2 positive macrophages substituted for Mac-2 negative macrophages, followed by CLS formation. All perilipin negative, dead adipocytes were surrounded by CLS structures. The time course of histopathology was similar in both fat pads studied, but occurred at earlier stages and was more gradual in mesenteric fat. Conclusion: Our data demonstrate that CLS formation results as a direct consequence of adipocyte death, and that infiltrating macrophages actively uptake remnant lipids of dead adipocytes. Upon induction of adipocyte apoptosis, inflammatory cells infiltrate adipose tissue initially consisting of neutrophils followed by macrophages that are involved in CLS formation.
AB - Background and aims: Crown-like structures (CLS) are characteristic histopathology features of inflamed adipose tissues in obese mice and humans. In previous work, we suggested that these cells derived from macrophages primarily involved in the reabsorption of dead adipocytes. Here, we used a well-characterized transgenic mouse model in which the death of adipocytes in adult mice is inducible and highly synchronized. In this "FAT ATTAC" model, apoptosis is induced through forced dimerization of a caspase-8 fusion protein. Methods and results: 0, 0.5, 1, 2, 3 and 10 days post induction of adipocyte cell death, we analyzed mesenteric and epididymal adipose depots by histology, immunohistochemistry and electron microscopy. Upon induction of caspase-8 dimerization, numerous adipocytes lost immunoreactivity for perilipin, a marker for live adipocytes. In the same areas, we found adipocytes with hypertrophic mitochondria and signs of organelle degeneration. Neutrophils and lymphocytes were the main inflammatory cells present in the tissue, and the macrophages were predominantly Mac-2 negative. Over the course of ablation, Mac-2 positive macrophages substituted for Mac-2 negative macrophages, followed by CLS formation. All perilipin negative, dead adipocytes were surrounded by CLS structures. The time course of histopathology was similar in both fat pads studied, but occurred at earlier stages and was more gradual in mesenteric fat. Conclusion: Our data demonstrate that CLS formation results as a direct consequence of adipocyte death, and that infiltrating macrophages actively uptake remnant lipids of dead adipocytes. Upon induction of adipocyte apoptosis, inflammatory cells infiltrate adipose tissue initially consisting of neutrophils followed by macrophages that are involved in CLS formation.
KW - Adipocytes
KW - Apoptosis
KW - CLS
KW - FAT ATTAC
KW - Fat
KW - Inflammation
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U2 - 10.1016/j.numecd.2012.03.005
DO - 10.1016/j.numecd.2012.03.005
M3 - Article
C2 - 22682975
AN - SCOPUS:84880046877
SN - 0939-4753
VL - 23
SP - 723
EP - 731
JO - Nutrition, Metabolism and Cardiovascular Diseases
JF - Nutrition, Metabolism and Cardiovascular Diseases
IS - 8
ER -