TY - JOUR
T1 - Adipocyte mTORC1 defciency promotes adipose tissue inflammation and NLRP3 inflammasome activation via oxidative stress and de novo ceramide synthesis
AU - Chimin, Patricia
AU - Andrade, Maynara L.
AU - Belchior, Thiago
AU - Paschoal, Vivian A.
AU - Magdalon, Juliana
AU - Yamashita, Alex S.
AU - Castro, Érique
AU - Castoldi, Angela
AU - Chaves-Filho, Adriano B.
AU - Yoshinaga, Marcos Y.
AU - Miyamoto, Sayuri
AU - Câmara, Niels O.
AU - Festuccia, William T.
N1 - Funding Information:
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo Grants 09/15354-7, 10/52191-6, and 15/19530-5 (to W.T.F) and 12/02270-2 (to N.O.C.) and Conselho Nacional de Desenvolvimento Científico e Tecnológico Grants 454226/2014-4 (to P.C.) and 443492/2014-0 (to W.T.F.). Additional support was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo Fellowships 12/25317-4 and 15/13508-8 (to P.C. and M.L.A., respectively). The authors do not have any potential conflicts of interest relevant to this article. Manuscript received 22 December 2016 and in revised form 13 June 2017. Published, JLR Papers in Press, July 5, 2017 DOI https://doi.org/10.1194/jlr.M074518
Publisher Copyright:
© 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017
Y1 - 2017
N2 - Mechanistic target of rapamycin complex (mTORC)1 activity is increased in adipose tissue of obese insulin-resistant mice, but its role in the regulation of tissue inflammation is unknown. Herein, we investigated the effects of adipocyte mTORC1 defciency on adipose tissue inflammation and glucose homeostasis. For this, mice with adipocyte raptor deletion and controls fed a chow or a high-fat diet were evaluated for body mass, adiposity, glucose homeostasis, and adipose tissue inflammation. Despite reducing adiposity, adipocyte mTORC1 defciency promoted hepatic steatosis, insulin resistance, and adipose tissue inflammation (increased infltration of macrophages, neutrophils, and B lymphocytes; crown-like structure density; TNF-fl, interleukin (IL)-6, and monocyte chemoattractant protein 1 expression; IL-1fl protein content; lipid peroxidation; and de novo ceramide synthesis). The anti-oxidant, N-acetylcysteine, partially attenuated, whereas treatment with de novo ceramide synthesis inhibitor, myriocin, completely blocked adipose tissue inflammation and nucleotide oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3)-inflammasome activation, but not hepatic steatosis and insulin resistance induced by adipocyte raptor deletion. Rosiglitazone treatment, however, completely abrogated insulin resistance induced by adipocyte raptor deletion. In conclusion, adipocyte mTORC1 defciency induces adipose tissue inflammation and NLRP3-inflammasome activation by promoting oxidative stress and de novo ceramide synthesis. Such adipose tissue inflammation, however, is not an underlying cause of the insulin resistance displayed by these mice.
AB - Mechanistic target of rapamycin complex (mTORC)1 activity is increased in adipose tissue of obese insulin-resistant mice, but its role in the regulation of tissue inflammation is unknown. Herein, we investigated the effects of adipocyte mTORC1 defciency on adipose tissue inflammation and glucose homeostasis. For this, mice with adipocyte raptor deletion and controls fed a chow or a high-fat diet were evaluated for body mass, adiposity, glucose homeostasis, and adipose tissue inflammation. Despite reducing adiposity, adipocyte mTORC1 defciency promoted hepatic steatosis, insulin resistance, and adipose tissue inflammation (increased infltration of macrophages, neutrophils, and B lymphocytes; crown-like structure density; TNF-fl, interleukin (IL)-6, and monocyte chemoattractant protein 1 expression; IL-1fl protein content; lipid peroxidation; and de novo ceramide synthesis). The anti-oxidant, N-acetylcysteine, partially attenuated, whereas treatment with de novo ceramide synthesis inhibitor, myriocin, completely blocked adipose tissue inflammation and nucleotide oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3)-inflammasome activation, but not hepatic steatosis and insulin resistance induced by adipocyte raptor deletion. Rosiglitazone treatment, however, completely abrogated insulin resistance induced by adipocyte raptor deletion. In conclusion, adipocyte mTORC1 defciency induces adipose tissue inflammation and NLRP3-inflammasome activation by promoting oxidative stress and de novo ceramide synthesis. Such adipose tissue inflammation, however, is not an underlying cause of the insulin resistance displayed by these mice.
KW - Insulin resistance
KW - Mechanistic target of rapamycin complex 1
KW - Nucleotide oligomerization domain-like receptor pyrin domaincontaining 3
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U2 - 10.1194/jlr.M074518
DO - 10.1194/jlr.M074518
M3 - Article
C2 - 28679588
AN - SCOPUS:85029409862
SN - 0022-2275
VL - 58
SP - 1797
EP - 1807
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 9
ER -