OBJECTIVE: We investigated whether PPARγ modulates adipose tissue BCAA metabolism, and whether this mediates the attenuation of obesity-associated insulin resistance induced by pharmacological PPARγ activation. METHODS: Mice with adipocyte deletion of one or two PPARγ 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 PPARγ 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 α-ketoacid dehydrogenase (BCKDH) complex subunits. Adipocyte deletion of two PPARγ copies induced lipodystrophy, severe glucose intolerance and markedly increased serum BCAA. Rosiglitazone abolished the increase in serum BCAA induced by adipocyte PPARγ 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: PPARγ, 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. PPARγ agonism, therefore, may improve whole-body and muscle insulin sensitivity by reducing blood BCAA, alleviating mTORC1-mediated inhibitory IRS1 phosphorylation.
OBJECTIVE: We investigated whether PPARγ modulates adipose tissue BCAA metabolism, and whether this mediates the attenuation of obesity-associated insulin resistance induced by pharmacological PPARγ activation. METHODS:Mice with adipocyte deletion of one or two PPARγ 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 PPARγ 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 α-ketoacid dehydrogenase (BCKDH) complex subunits. Adipocyte deletion of two PPARγ copies induced lipodystrophy, severe glucose intolerance and markedly increased serum BCAA. Rosiglitazone abolished the increase in serum BCAA induced by adipocyte PPARγ 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: PPARγ, 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. PPARγ agonism, therefore, may improve whole-body and muscle insulin sensitivity by reducing blood BCAA, alleviating mTORC1-mediated inhibitory IRS1 phosphorylation.
Authors: Mona S Nilsen; Regine Å Jersin; Arve Ulvik; André Madsen; Adrian McCann; Per-Arne Svensson; Maria K Svensson; Bjørn G Nedrebø; Oddrun A Gudbrandsen; Grethe S Tell; C R Kahn; Per M Ueland; Gunnar Mellgren; Simon N Dankel Journal: Diabetes Date: 2020-06-25 Impact factor: 9.461
Authors: Maynara L Andrade; Gustavo R Gilio; Luiz A Perandini; Albert S Peixoto; Mayara F Moreno; Érique Castro; Tiago E Oliveira; Thayna S Vieira; Milene Ortiz-Silva; Caroline A Thomazelli; Adriano B Chaves-Filho; Thiago Belchior; Patricia Chimin; Juliana Magdalon; Rachael Ivison; Deepti Pant; Linus Tsai; Marcos Y Yoshinaga; Sayuri Miyamoto; William T Festuccia Journal: Biochim Biophys Acta Mol Cell Biol Lipids Date: 2021-05-15 Impact factor: 5.228
Authors: Elma Zaganjor; Haejin Yoon; Jessica B Spinelli; Elizabeth R Nunn; Gaëlle Laurent; Paulina Keskinidis; Suganja Sivaloganathan; Shakchhi Joshi; Giulia Notarangelo; Stacy Mulei; Mathew T Chvasta; Sarah A Tucker; Krystle Kalafut; Robert A H van de Ven; Clary B Clish; Marcia C Haigis Journal: Cell Rep Date: 2021-07-13 Impact factor: 9.423