FoxO Forkhead transcription factors are major targets of insulin action and may play an important role in the pathogenesis of diabetes mellitus, a major cause of morbidity and mortality in the Veteran population. FoxO proteins play an important role in promoting hepatic glucose production, and the ability of insulin to suppress FoxO activity is thought to be important in maintaining glucose homeostasis. Based on studies in transgenic mice, we reported that FoxO proteins also contribute to the regulation of other metabolic functions in the liver, including lipd metabolism, and recent studies in knock in and knock out models support this concept. We previously found that transgenic expression of constitutively active FoxO1 suppressed the expression of SREBP-1c (a master regulator of lipogenic gene expression) and de novo lipogenesis (measured with 3H- tagged H2O) after eating, yet the mechanisms mediating this effect remain unclear. Based on recent findings, we have identified a novel mechanism that promises to shed new light onto the pathway mediating FoxO effects on lipid metabolism. Additional studies are planned to investigate specific mechanisms mediating effects of FoxO proteins on gene expression and metabolism in the liver.

Public Health Relevance

Diabetes mellitus and disorders of lipid metabolism are major causes of morbidity and metabolism in the Veteran population. Research in this laboratory focuses on understanding mechanisms regulating glucose and lipid metabolism at the molecular level. Previous studies in this and other laboratories have shown that FoxO transcription factors directly interact with genes promoting glucose production and mediate effects of insulin on glucose metabolism in the liver. We also have found that FoxO proteins exert potent effects on lipid metabolism in the liver, yet the mechanisms mediating this effect remain unclear. Based on recent findings, we have identified a novel mechanism that promises to shed new light onto the pathway mediating FoxO effects on lipid metabolism. The results of this research may provide new insight into mechanisms regulating lipid metabolism in the liver, and lead to the development of new strategies for treating lipid disorders and diabetes.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Endocriniology A (ENDA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Jesse Brown VA Medical Center
United States
Zip Code
Fernandes, Gustavo W; Bocco, Barbara M L C; Fonseca, Tatiana L et al. (2018) The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia. Cell Rep 22:523-534
Valitsky, Michael; Hoffman, Amnon; Unterman, Terry et al. (2017) Insulin sensitizer prevents and ameliorates experimental type 1 diabetes. Am J Physiol Endocrinol Metab 313:E672-E680
Zhang, Wenwei; Bu, So Young; Mashek, Mara T et al. (2016) Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins. Cell Rep 15:349-59
Bhattacharyya, Sumit; Feferman, Leo; Unterman, Terry et al. (2015) Exposure to common food additive carrageenan alone leads to fasting hyperglycemia and in combination with high fat diet exacerbates glucose intolerance and hyperlipidemia without effect on weight. J Diabetes Res 2015:513429
Chung, Sangwoon; Ranjan, Ravi; Lee, Yong Gyu et al. (2015) Distinct role of FoxO1 in M-CSF- and GM-CSF-differentiated macrophages contributes LPS-mediated IL-10: implication in hyperglycemia. J Leukoc Biol 97:327-39
O-Sullivan, InSug; Zhang, Wenwei; Wasserman, David H et al. (2015) FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat Commun 6:7079
Bhat, Uppoor G; Ilievski, Vladimir; Unterman, Terry G et al. (2014) Porphyromonas gingivalis lipopolysaccharide upregulates insulin secretion from pancreatic ? cell line MIN6. J Periodontol 85:1629-36
Barnosky, Adrienne R; Hoddy, Kristin K; Unterman, Terry G et al. (2014) Intermittent fasting vs daily calorie restriction for type 2 diabetes prevention: a review of human findings. Transl Res 164:302-11