Type 2 diabetes (T2DM) is a life-threatening disease characterized by hepatic and peripheral insulin resistance, which dysregulate inter-tissue metabolic flux and communication to promote hyperglycemia and dyslipidemia. Insulin signaling throughout the body is mediated by the insulin receptor substrate proteins IRS1 and IRS2. Within the liver, insulin regulates gene expression and metabolism largely via the IRS-dependent inhibition of transcription factor FoxO1. This renewal is founded on the striking observation that hepatic insulin resistance in ?LDKO? mice?which lack Irs1 and Irs2 in liver?propagates insulin resistance to the skeletal muscle and white and brown adipose tissues (WAT and BAT). Excessive hepatic glucose production (HGP) during diabetes owes, at least in part, to hepatic insulin resistance and activation of gluconeogenic genes by FoxO1. However, HGP is normalized in LDKO-mice upon inactivation/deletion of hepatic FoxO1 (i.e., ?LTKO? mice), suggesting that unknown, FoxO1-dependent factors secreted by the liver (?hepatokines?) act to promote insulin resistance in peripheral tissues. This competitive renewal focuses upon the dysregulated hepatokines in LDKO liver to reveal how peripheral metabolic disease depends upon FoxO1?rather than hepatic insulin signaling per se. This is an innovative departure from the study of a single tissue or pathway that can, moreover, reveal the mechanisms by which hepatic resistance alone gives rise to many of the features of T2DM in mice. Robust preliminary data allow us to focus upon functionally important hepatokines that are elevated or decreased in LDKO liver, but normalized in LTKO liver. In addition to increased cardiovascular disease risk, T2DM is associated with non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH) and eventual hepatocellular carcinoma (HCC); we have further established that this progression is attenuated in LTKO mice. Using deletion of floxed hepatokine alleles?or hepatotropic AAV (adeno-associated virus) to knock-down or over-express hepatokine genes?we employ both LDKO and LTKO mice to reveal (and corroborate) the effects of dysregulated FoxO1-dependent hepatokines upon systemic nutrient homeostasis and the progression of liver disease.

Public Health Relevance

Progressive hepatic and peripheral insulin resistance is an underlying cause of both fatty liver disease and type 2 diabetes. The goal of this project is to investigate mechanisms by which hepatic insulin resistance - caused by the deletion of proximal insulin signaling components - causes extrahepatic peripheral insulin resistance and progressive liver disease. In this renewal, we use our unique mouse models to investigate the role of hepatocyte-secreted proteins (hepatokines) in the propagation of peripheral insulin resistance and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK098655-06
Application #
9533539
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
Project Start
2013-04-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
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

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