Adipocyte mTORC1 defciency promotes adipose tissue inflammation and NLRP3 inflammasome activation via oxidative stress and de novo ceramide synthesis

Patricia Chimin, Maynara L. Andrade, Thiago Belchior, Vivian A. Paschoal, Juliana Magdalon, Alex S. Yamashita, Érique Castro, Angela Castoldi, Adriano B. Chaves-Filho, Marcos Y. Yoshinaga, Sayuri Miyamoto, Niels O. Câmara, William T. Festuccia

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1797-1807
Number of pages11
JournalJournal of Lipid Research
Volume58
Issue number9
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Insulin resistance
  • Mechanistic target of rapamycin complex 1
  • Nucleotide oligomerization domain-like receptor pyrin domaincontaining 3

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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