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Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis.
Perry, Rachel J; Zhang, Dongyan; Guerra, Mateus T; Brill, Allison L; Goedeke, Leigh; Nasiri, Ali R; Rabin-Court, Aviva; Wang, Yongliang; Peng, Liang; Dufour, Sylvie; Zhang, Ye; Zhang, Xian-Man; Butrico, Gina M; Toussaint, Keshia; Nozaki, Yuichi; Cline, Gary W; Petersen, Kitt Falk; Nathanson, Michael H; Ehrlich, Barbara E; Shulman, Gerald I.
Afiliação
  • Perry RJ; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Zhang D; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.
  • Guerra MT; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Brill AL; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Goedeke L; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.
  • Nasiri AR; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Rabin-Court A; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Wang Y; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Peng L; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Dufour S; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Zhang Y; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Zhang XM; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Butrico GM; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Toussaint K; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Nozaki Y; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Cline GW; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Petersen KF; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Nathanson MH; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Ehrlich BE; Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Shulman GI; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.
Nature ; 579(7798): 279-283, 2020 03.
Article em En | MEDLINE | ID: mdl-32132708
Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glucagon / Receptores de Inositol 1,4,5-Trifosfato / Gluconeogênese / Fígado Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glucagon / Receptores de Inositol 1,4,5-Trifosfato / Gluconeogênese / Fígado Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article