This is a new proposal entitled """"""""Hepatic insulin resistance and metabolic disease"""""""" that is based upon work conducted in our laboratory during the past 5 years with LDKO (hepatic-specific Irs1-/-""""""""Irs2-/-) and LTKO (hepatic-specific Irs1-/-""""""""Irs2-/-""""""""FoxO1-/-) mice. LDKO-mice display systemic metabolic dysregulation, including hepatic and peripheral insulin resistance, hyperglycemia, moderate hyperinsulinemia, and progressive NAFLD (nonalcoholic fatty liver disease). The etiology of NAFLD is rooted in insulin resistance, obesity, hyperlipidemia, and diabetes. As LTKO-mice display normal nutrient homeostasis, we posit that activated hepatic FoxO1, rather than the mere accumulation of hepatic triglyceride, promotes inflammation that progresses to life- threatening necrosis/apoptosis and cycles of regeneration that culminate with damage-characteristic of the progression of NAFLD to NASH (nonalcoholic steatohepatitis) and HCC (hepatocellular carcinoma). To investigate the underlying pathophysiology, we focus upon mitochondrial dysfunction that develops as a result of chronically activated FoxO1 that increases the expression of hundreds of genes, including hemeoxygenase- 1 (encoded by Hmox1) and cyclophilin D (encoded by Ppif). To interrogate the molecular mechanisms, we propose to use nanoparticle delivery of targeted siRNA to suppress the expression of hepatic FoxO1, Hmox1, or Ppif during initiation (10 weeks of age) and progression (10 months of age) of NAFLD. To enable this technology in our laboratory, we have formed a 'Consortium Agreement'with the Amiji group in the School of Pharmacy at Northeastern University. The mouse-based experiments will investigate the relation between FoxO1-mediated hepatic mitochondrial dysfunction and progressive NAFLD/NASH upon systemic inflammation and muscle insulin action that contributes to diabetes in the following Specific Aims: i) Investigate FoxO1-mediated mitochondrial dysfunction in LDKO-mice by modulating the expression of FoxO1, Hmox1 or Ppif to restore mitochondrial function and attenuate hepatic inflammation, NASH and its progression to HCC during persistent hepatic insulin resistance. ii) Investigate skeletal muscle insulin resistance in LDKO-mice to establish the relation between hepatic inflammation and dysregulated skeletal muscle insulin action and metabolism. iii) Quantify Ser/Thr-phosphorylation of IRS1 in muscle of LDKO-mice using a library of phosphosite-specific monoclonal antibodies before and after resolution of hepatic mitochondrial dysfunction and NAFLD by suppression of FoxO1, Hmox1 or Ppif. Since the LDKO-mice are uncomplicated by the dominant effects of hypothalamic-based obesity encountered with ob/ob-mice, our experiments focus squarely upon the relation between hepatic insulin resistance and NAFLD, and its progression to systemic insulin resistance and diabetes.

Public Health Relevance

Diabetes complicated by nonalcoholic fatty liver disease is a major health problem around the world that develops hepatic insulin resistance is exacerbated by dysregulated insulin secretion from pancreatic beta-cells needed to maintain optimal nutrient homeostasis. It is crucial to investigate the underlying molecular basis of NAFLD and it relation to diabetes in order to identify effective and safe treatment strategies. The experiments proposed in this application investigate how dysregulated hepatic insulin signaling, in the absence of hypothalamic obesity, contributes to NAFLD and peripheral insulin resistance. New treatment targets can be validated through the studies outlined in the proposal.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Silva, Corinne M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
Xu, He; Lee, Min-Sik; Tsai, Pei-Yun et al. (2018) Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis. Proc Natl Acad Sci U S A 115:4228-4233
Tao, Rongya; Wang, Caixia; Stöhr, Oliver et al. (2018) Inactivating hepatic follistatin alleviates hyperglycemia. Nat Med 24:1058-1069
Long, Yun Chau; Cheng, Zhiyong; Copps, Kyle D et al. (2017) Correction for Long et al., ""Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways"". Mol Cell Biol 37:
Cao, Jia; Peng, Jinghua; An, Hongying et al. (2017) Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity. Nat Commun 8:131
Xi, Gang; Wai, Christine; White, Morris F et al. (2017) Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation. J Biol Chem 292:2009-2020
Kuznetsova, Alexandra; Yu, Yue; Hollister-Lock, Jennifer et al. (2016) Trimeprazine increases IRS2 in human islets and promotes pancreatic ? cell growth and function in mice. JCI Insight 1:
Copps, Kyle D; Hançer, Nancy J; Qiu, Wei et al. (2016) Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase. J Biol Chem 291:8602-17
Law, Nathan C; White, Morris F; Hunzicker-Dunn, Mary E (2016) G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway. J Biol Chem 291:27160-27169
White, Morris F (2015) Longevity: Mapping the path to a longer life. Nature 524:170-1
Hançer, Nancy J; Qiu, Wei; Cherella, Christine et al. (2014) Insulin and metabolic stress stimulate multisite serine/threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation. J Biol Chem 289:12467-84

Showing the most recent 10 out of 25 publications