PPAR gamma is a major regulator of branched-chain amino acid blood levels and catabolism in white and brown adipose tissues

Author(s):Show less -

Blanchard, Pierre-Gilles ^[1] ; Moreira, Rafael J. ^[2] ; Castro, Erique ^[2] ; Caron, Alexandre ^[1] ; Cote, Marie ^[1] ; Andrade, Maynara L. ^[2] ; Oliveira, Tiago E. ^[2] ; Ortiz-Silva, Milene ^[2] ; Peixoto, Albert S. ^[2] ; Dias, France Anne ^[3] ; Gelinas, Yves ^[1] ; Guerra-Sa, Renata ^[3] ; Deshaies, Yves ^[1] ; Festuccia, William T. ^[2]

Affiliation

^[1] Laval Univ, Quebec Heart & Lung Inst, Fac Med, Dept Med, Quebec City, PQ - Canada

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Ave Prof Lineu Prestes 1524, BR-05508000 Sao Paulo - Brazil

^[3] Univ Fed Ouro Preto, Dept Biol Sci, ICEB, Ouro Preto - Brazil

• Document type: Journal article
• Source: METABOLISM-CLINICAL AND EXPERIMENTAL; v. 89, p. 27-38, DEC 2018.
• Web of Science Citations: 5

Abstract

Objective: We investigated whether PPAR gamma modulates adipose tissue BCAA metabolism, and whether this mediates the attenuation of obesity-associated insulin resistance induced by pharmacological PPAR gamma activation. Methods: Mice with adipocyte deletion of one or two PPAR gamma copies fed a chow diet and rats fed either chow, or high fat (HF) or HF supplemented with BCAA (HF/BCAA) diets treated with rosiglitazone (30 or 15 mg/kg/day, 14 days) were evaluated for glucose and BCAA homeostasis. Results: Adipocyte deletion of one PPAR gamma copy increased mice serum BCAA and reduced inguinal white (iWAT) and brown (BAT) adipose tissue BCAA incorporation into triacylglycerol, as well as mRNA levels of branched chain aminotransferase (BCAT)2 and branched-chain alpha-Retoacid dehydrogenase (BCKDH) complex subunits. Adipocyte deletion of two PPAR gamma copies induced lipodystrophy, severe glucose intolerance and markedly increased serum BCAA. Rosiglitazone abolished the increase in serum BCAA induced by adipocyte PPAR gamma deletion. In rats, HF increased serum BCAA, such levels being further increased by BCAA supplementation. Rosiglitazone, independently of diet, lowered serum BCAA and upregulated iWAT and BAT BCAT and BCKDH activities. This was associated with a reduction in mTORC1-dependent inhibitory serine phosphorylation of IRS1 in skeletal muscle and whole-body insulin resistance evaluated by HOMA-IR. Conclusions: PPAR gamma, through the regulation of both BAT and iWAT BCAA catabolism in lipoeutrophic mice and muscle insulin responsiveness and proteolysis in lipodystrophic mice, is a major determinant of circulating BCAA levels. PPAR gamma agonism, therefore, may improve whole-body and muscle insulin sensitivity by reducing blood BCAA, alleviating mTORC1-mediated inhibitory IRS1 phosphorylation. (C) 2018 Elsevier Inc. All rights reserved. (AU)

• 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: 16/07062-0 - Characterization of the mechanisms underlying omega-3 fatty acids effects on energy balance
• Grantee: Tiago Eugênio Oliveira da Silva
• Support Opportunities: Scholarships in Brazil - Master
• 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
• Grantee: Milene Ortiz Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• 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: 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