PPAR gamma-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activity

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Andrade, Maynara L. ; Gilio, Gustavo R. ; Perandini, Luiz A. ; Peixoto, Albert S. ; Moreno, Mayara F. ; Castro, Erique ; Oliveira, Tiago E. ; Vieira, Thayna S. ; Ortiz-Silva, Milene ; Thomazelli, Caroline A. ; Chaves-Filho, Adriano B. ; Belchior, Thiago ; Chimin, Patricia ; Magdalon, Juliana ; Ivison, Rachael ; Pant, Deepti ; Tsai, Linus ; Yoshinaga, Marcos Y. ; Miyamoto, Sayuri ; Festuccia, William T.

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS; v. 1866, n. 8, p. 11-pg., 2021-05-19.

Abstract

The nutrient sensors peroxisome proliferator-activated receptor. (PPAR gamma) and mechanistic target of rapamycin complex 1 (mTORC1) closely interact in the regulation of adipocyte lipid storage. The precise mechanisms underlying this interaction and whether this extends to other metabolic processes and the endocrine function of adipocytes are still unknown. We investigated herein the involvement of mTORC1 as a mediator of the actions of the PPAR gamma ligand rosiglitazone in subcutaneous inguinal white adipose tissue (iWAT) mass, endocrine function, lipidome, transcriptome and branched-chain amino acid (BCAA) metabolism. Mice bearing regulatory associated protein of mTOR (Raptor) deletion and therefore mTORC1 deficiency exclusively in adipocytes and littermate controls were fed a high-fat diet supplemented or not with the PPAR gamma agonist rosiglitazone (30 mg/kg/day) for 8 weeks and evaluated for iWAT mass, lipidome, transcriptome (Rnaseq), respiration and BCAA metabolism. Adipocyte mTORC1 deficiency not only impaired iWAT adiponectin transcription, synthesis and secretion, PEPCK mRNA levels, triacylglycerol synthesis and BCAA oxidation and mRNA levels of related proteins but also completely blocked the upregulation in these processes induced by pharmacological PPAR gamma activation with rosiglitazone. Mechanistically, adipocyte mTORC1 deficiency impairs PPAR gamma transcriptional activity by reducing PPAR gamma protein content, as well as by downregulating C/EBP alpha, a co-partner and facilitator of PPAR gamma. In conclusion, mTORC1 and PPAR gamma are essential partners involved in the regulation of subcutaneous adipose tissue adiponectin production and secretion and BCAA oxidative metabolism. (AU)

• FAPESP's process: 19/17660-0 - Discovery of new transcription factors involved in the development of steatosis, steatopatite and hepatocarcinome
• Grantee: Luiz Augusto Buoro Perandini
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/23169-9 - Involvement of mTORC1 and 2 and PPARgamma in the regulation of leukocyte profile, recruitment and activation of brown adipose tissue and beige adipocytes induced by cold exposure
• Grantee: Érique de Castro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/23040-9 - Characterization of mTORC2 role in the hepatic steatosis, steatohepatitis and hepatocellular carcinoma progression induced by PTEN deletion in hepatocytes
• Grantee: Álbert Souza Peixoto
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/22983-1 - Discovery of new transcription factors involved in the development of steatosis, steatohepatitis, and liver cancer
• Grantee: Thiago Belchior de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/17403-1 - Characterization of the molecular mechanisms by which TSC1 deletion in adipocytes increases oxidative metabolism and UCP1 content in white adipose tissue
• Grantee: Thayna dos Santos Vieira
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
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• Grantee: Tiago Eugênio Oliveira da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
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• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/17582-3 - Characterization of the involvement of nutrient sensor mTORC1 in the hepatic steatosis, steatohepatitis, and hepatocarcinoma induced by PTEN deletion into hepatocytes
• Grantee: Mayara Franzoi Moreno
• 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: 17/12260-8 - Autophagy involvement in the metabolic and inflammatory alterations in adipose tissue associated with Obesity induced by high fat diet
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• FAPESP's process: 18/11156-5 - Effects of obesity and severe lipodystrophy on oxidation and peroxidation of lipids: involvement of these molecules on inflammation and insulin resistance
• Grantee: Adriano de Britto Chaves Filho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• 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: 19/01763-4 - Characterization of the molecular mechanisms determining the energy balance, glucose homeostasis and hepatomegaly in mice with severe lipodystrophy
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• Support Opportunities: Regular Research Grants