Insulin resistance is an important risk factor for alcoholic liver disease (ALD). Vice versa, heavy alcohol consumption induces insulin resistance that is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Insulin is the key hormone that regulates lipid and glucose metabolism; it is also an important regulator of inflammation. Thus, hepatic insulin action is likely a key player in the pathogenesis of ALD, yet the mechanisms through which impaired insulin action predisposes to ALD remain poorly understood. We and others have previously demonstrated that insulin signaling within the mediobasal hypothalamus (MBH) controls hepatic glucose production (hGP), very low density lipoprotein (VLDL) secretion, white adipose tissue (WAT) lipolysis and innate immunity through the autonomic nervous system. Based on our pilot data that demonstrate that in a rat model for binge drinking, i.e. short term alcohol consumption impairs glucose tolerance and induces insulin resistance that is due to impaired hepatic insulin action. Binge drinking markedly impairs hypothalamic insulin action, defined as the ability of hypothalamic insulin to suppress hGP and adipose tissue lipolysis. Thus, the major hypothesis proposed in this proposal is that some of the metabolic and innate immunity defects induced by alcohol are caused through brain effects disrupting autonomic control of both metabolism and innate immunity. In support ofthis novel paradigm we find that a central cause ofthe impaired hypothalamic insulin action is decreased insulin signaling in the hypothalamus likely due to increased inflammation, ER stress and expression of protein tyrosine phosphatase l b (PTPIb), a negative regulator of insulin signaling. Here we propose to delineate the mechanisms through which chronic alcohol consumption impairs insulin action, disrupts hepatic carbohydrate, amino acid and lipid metabolism and generates a pro-inflammatory environment within the liver that predisposes to ALD.

Public Health Relevance

Chronic alcohol consumption can cause alcoholic liver disease (ALD). In this proposal we aim to investigate the role of the neurotoxic effects of alcohol in impairing hepatic metabolism and if a prevention of the brain effects of alcohol can prevent liver disease. These studies will advance our understanding of how alcoholism leads to ALD and may identify strategies to prevent ALD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
3R01AA023416-04S1
Application #
9530801
Study Section
Program Officer
Orosz, Andras
Project Start
2017-07-24
Project End
2018-01-31
Budget Start
2017-07-24
Budget End
2018-01-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Fischer, Katrin; Ruiz, Henry H; Jhun, Kevin et al. (2017) Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 23:623-630
Scherer, Thomas; Wolf, Peter; Smajis, Sabina et al. (2017) Chronic Intranasal Insulin Does Not Affect Hepatic Lipids but Lowers Circulating BCAAs in Healthy Male Subjects. J Clin Endocrinol Metab 102:1325-1332
Shin, Andrew C; Filatova, Nika; Lindtner, Claudia et al. (2017) Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action. Diabetes 66:1560-1571
Oberlin, Douglas; Buettner, Christoph (2017) How does leptin restore euglycemia in insulin-deficient diabetes? J Clin Invest 127:450-453
Jiang, Cheng; Lin, Wei-Jye; Sadahiro, Masato et al. (2017) Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight. Neuropeptides 64:75-83
Liu, Peng; Ji, Yaoting; Yuen, Tony et al. (2017) Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546:107-112
Langlet, Fanny; Haeusler, Rebecca A; Lindén, Daniel et al. (2017) Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling. Cell 171:824-835.e18
La Merrill, Michele A; Sethi, Sunjay; Benard, Ludovic et al. (2016) Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice. Environ Health Perspect 124:1722-1727
Kang, Soojeong; Dahl, Russell; Hsieh, Wilson et al. (2016) Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders. J Biol Chem 291:5185-98
Scherer, Thomas; Lindtner, Claudia; O'Hare, James et al. (2016) Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain. Diabetes 65:1511-20

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