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.
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.
|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|
|Liu, Peng; Ji, Yaoting; Yuen, Tony et al. (2017) Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546:107-112|
|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|
|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|
|Ruiz, Henry H; Chi, Tiffany; Shin, Andrew C et al. (2016) Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimers Dement 12:851-61|
|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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