Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins

Wenwei Zhang, So Young Bu, Mara T. Mashek, In Sug O-Sullivan, Zakaria Sibai, Salmaan A. Khan, Olga Ilkayeva, Christopher B. Newgard, Douglas G. Mashek, Terry G. Unterman

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the liver. However, the mechanisms by which FoxO proteins exert these diverse effects in an integrated fashion remain poorly understood. We report that FoxO proteins also exert important effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the G0/S1 switch 2 gene (G0S2). We also find that ATGL-dependent lipolysis plays a critical role in mediating diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic, and lipogenic gene expression and metabolism. These results indicate that intrahepatic lipolysis plays a critical role in mediating and integrating the regulation of glucose and lipid metabolism downstream of FoxO proteins.

Original languageEnglish (US)
Pages (from-to)349-359
Number of pages11
JournalCell reports
Volume15
Issue number2
DOIs
StatePublished - Apr 12 2016

Bibliographical note

Funding Information:
This research was supported in part by grants from the Department of Veterans Affairs Merit Review Program (to T.G.U.) and NIH grants DK58398 (to C.B.N.), DK085008 (to D.G.M.), DK059630 (to University of Cincinnati Mouse Metabolic Phenotyping Center), UL1TR000439 (to CASE MMPC), and DK050456 (to Minnesota Obesity Center). The authors thank Drs. Jacob Bartana and Stanley Blumenthal for helpful comments and discussion, Dr. Michelle Pucholwicz for guidance in planning and analysis of studies related to lipogenesis, and Daniel Glick-Unterman for graphical support.

Funding Information:
This research was supported in part by grants from the Department of Veterans Affairs Merit Review Program (to T.G.U.) and NIH grants DK58398 (to C.B.N.), DK085008 (to D.G.M.), DK059630 (to University of Cincinnati Mouse Metabolic Phenotyping Center), UL1TR000439 (to CASE MMPC), and DK050456 (to Minnesota Obesity Center). The authors thank Drs. Jacob Bartana and Stanley Blumenthal for helpful comments and discussion, Dr. Michelle Pucholwicz for guidance in planning and analysis of studies related to lipogenesis, and Daniel Glick-Unterman for graphical support.

Publisher Copyright:
© 2016 The Authors.

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