In this competing renewal a team of interdisciplinary investigators, who have an established track record of collaboration, will examine the cellular and molecular mechanisms of lipid-induced hepatic insulin resistance. Recent studies in both humans and rodent models of non alcoholic fatty liver disease (NAFLD) have led to a unifying diacylglycerol-hypothesis (DAG-hypothesis) for lipid-induced hepatic insulin resistance where accumulation of intracellular DAG activates protein kinase C5 (PKC5), directly leading to inhibition of insulin- stimulated insulin receptor kinase (IRK) activity.
Specific Aim 1 wil explore the molecular mechanism by which activation of PKC5 leads to inhibition of IRK activity.
This aim wil examine the hypothesis that PKC5 activation promotes increased threonine phosphorylation of IRK, which in turn blocks insulin-stimulated IRK activity, utilizing state-of-the-art LC-MS/MS methods to identify novel PKC5-induced IRK phosphothreonine sites.
Specific Aim 2 wil further examine the DAG-hypothesis by examining the effect of a potential novel therapeutic target (INDY, acronym for I am Not Dead, Yet) on lipid-induced hepatic insulin resistance in awake whole body INDY knockout mice as well as awake rats with liver specific knockdown expression of INDY utilizing mRNA selective antisense oligonucleotides. INDY encodes a non-electrogenic dicarboxylate and citrate transporter and has been shown to promote longevity in a manner akin to caloric restriction in flies, but its role in mammals is unknown.
This aim builds on our strong preliminary data demonstrating that INDY knockout mice exhibit increased whole body energy expenditure and are protected from lipid-induced whole body insulin resistance.
Specific Aim 3 wil examine the mechanism by which knockdown of INDY in liver leads to increased whole body energy expenditure by employing a novel state-of-the-art 13C/31P NMR method to measure in vivo rates of hepatic fat oxidation, hepatic pyruvate oxidation, hepatic mitochondrial TCA flux, hepatic mitochondrial ATP synthesis and hepatic mitochondrial energy coupling in awake rats for the first time.
This aim will examine the hypothesis that decreased hepatic expression of INDY will result in increased rates of hepatic mitochondrial TCA flux, increased rates of hepatic fatty acid oxidation, and decreased hepatic mitochondrial energy coupling, which results in lower hepatic DAG content and protection from lipid-induced hepatic insulin resistance. It is anticipated that the results from these studies will provide important new insights into the cellular mechanisms of NAFLD associated hepatic insulin resistance as well as the identification of a novel therapeutic target for the treatment of NALFD and T2D. Furthermore, once validated in these animal experiments, these 13C/31P NMR methods will be translated to man to directly assess liver specific rates of hepatic mitochondrial TCA flux, mitochondrial ATP synthesis and hepatic mitochondrial energy coupling in humans for the first time.
Hepatic insulin resistance, associated with non alcoholic fatty liver disease (NAFLD), is a major factor responsible for the development of type 2 diabetes (T2D), which currently affects 11.3% of adults and is projected to affect as many as 1 in 3 Americans by 2050. It is anticipated that the results from these studies will provide important new insights into the cellular mechanisms by which NAFLD causes hepatic insulin resistance as well as the identification of a novel therapeutic target to treat NALFD and T2D.
|Qiu, Yang; Perry, Rachel J; Camporez, João-Paulo G et al. (2018) In vivo studies on the mechanism of methylene cyclopropyl acetic acid and methylene cyclopropyl glycine-induced hypoglycemia. Biochem J 475:1063-1074|
|Jelenik, Tomas; Flögel, Ulrich; Álvarez-Hernández, Elisa et al. (2018) Insulin Resistance and Vulnerability to Cardiac Ischemia. Diabetes 67:2695-2702|
|Gassaway, Brandon M; Petersen, Max C; Surovtseva, Yulia V et al. (2018) PKC? contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proc Natl Acad Sci U S A 115:E8996-E9005|
|Corbit, Kevin C; Camporez, João Paulo G; Edmunds, Lia R et al. (2018) Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling. Diabetes 67:208-221|
|Perry, Rachel J; Peng, Liang; Cline, Gary W et al. (2018) Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes. Cell Metab 27:210-217.e3|
|Samuel, Varman T; Shulman, Gerald I (2018) Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab 27:22-41|
|Price, Nathan L; Singh, Abhishek K; Rotllan, Noemi et al. (2018) Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance. Cell Rep 22:2133-2145|
|Perry, Rachel J; Wang, Yongliang; Cline, Gary W et al. (2018) Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation. Cell 172:234-248.e17|
|Vatner, Daniel F; Goedeke, Leigh; Camporez, Joao-Paulo G et al. (2018) Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. Diabetologia 61:1435-1446|
|Wang, Yongliang; Nasiri, Ali R; Damsky, William E et al. (2018) Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer. Cell Rep 24:47-55|
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