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

Author(s):Show less -

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

• Document type: Journal article
• Source: Journal of Lipid Research; v. 58, n. 9, p. 1797-1807, SEP 2017.
• Web of Science Citations: 11

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 deficiency 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 deficiency promoted hepatic steatosis, insulin resistance, and adipose tissue inflammation (increased infiltration of macrophages, neutrophils, and B lymphocytes; crown-like structure density; TNF-., interleukin (IL)-6, and monocyte chemoattractant protein 1 expression; IL-1. 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 deficiency 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.-Chimin, P., M. L. Andrade, T. Belchior, V. A. Paschoal, J. Magdalon, A. S. Yamashita, E. Castro, A. Castoldi, A. B. Chaves-Filho, M. Y. Yoshinaga, S. Miyamoto, N. O. Camara, and W. T. Festuccia. Adipocyte mTORC1 deficiency promotes adipose tissue inflammation and NLRP3 inflammasome activation via oxidative stress and de novo ceramide synthesis. (AU)

• FAPESP's process: 12/25317-4 - Involvement of mTOR complex 1 and 2 in secretory control of lipid and protein inflammatory mediators by adipocytes in obesity and insulin resistance conditions.
• Grantee: Patricia Chimin
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/19530-5 - Involvement of the nutrient sensor mTOR in the development of obesity associated chronic metabolic diseases
• Grantee: William Tadeu Lara Festuccia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/13508-8 - Involvement of adipocytes mTOR complexes 1 and 2 in the morphological, metabolic and secretory changes induced by pharmacological PPARgamma activation
• Grantee: Maynara Lucca Andrade
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 09/15354-7 - Role of adipose tissue in the development of obesity and associated co-morbidities: investigation of molecular mechanism and search for alternative therapies
• Grantee: William Tadeu Lara Festuccia
• Support Opportunities: Research Grants - Young Investigators Grants