This exploratory project will test the hypothesis that chronic alcohol consumption impairs the thermogenic capacity of brown adipose tissue (BAT), and that this impairment is associated with alcohol's effect on BAT retinoid metabolism. The project has two Specific Aims, the first is designed to assess the functional impairment associated with chronic alcohol consumption on BAT, and the second will provide mechanistic insight into the effects of alcohol in this tissue. The results of this project will be of broad significance to 3 research areas: research on alcoholism, BAT physiology, and retinoid homeostasis. The concept that BAT has physiological functions in adult humans represents a paradigm shift in the field of BAT research, and has led to an increased interest in this hitherto underappreciated tissue. Our preliminary data reveal that chronic alcohol consumption is associated with a dysregulation of body temperature maintenance, as well as a very marked decrease in BAT mass.
In Specific Aim 1 the functional consequences of chronic alcohol consumption on BAT thermogenesis will be systematically investigated. Through a series of alcohol-feeding studies, we will assess the effects of alcohol-feeding on BAT morphology and function. The thermogenic capacity of alcohol-fed mice will be tested using 2 established techniques: responsiveness to cold exposure, and responsiveness to a norepinehprine challenge. We expect to establish that chronic alcohol consumption has a negative impact on the thermogenic capacity of BAT in adult mice.
While Specific Aim 1 is designed to characterize the effect that alcohol feeding has on BAT function, Specific Aim 2 is designed to provide a mechanistic insight into this effect. Specifically, in Specific Aim 2 we will test the hypothesis tat alcohol-induced dysregulation of retinoid metabolism contributes to alcohol- induced alterations in BAT physiology. This hypothesis has its origins in the established effects that retinoids have on BAT differentiation and function, as well as our preliminary data which indicates that BAT of alcohol-fed mice has altered tissue retinoid levels, as well as changes in the gene expression levels of genes important in retinoid metabolism. We plan to undertake a comprehensive analysis of retinoid metabolism in BAT of alcohol-fed mice;we will also perform alcohol-feeding experiments in which the dietary retinoid content has been altered. We expect that the data obtained from these experiments will confirm our hypothesis that alcohol consumption disrupts BAT retinoid homeostasis, with a consequent effect on BAT function. In summary, the research proposed in this R21 application will explore the novel concept that chronic alcohol consumption affects the body's ability to produce heat through its effect on BAT. The data generated regarding these innovative hypotheses will impact general concepts regarding the effects of alcohol consumption on tissues other than the liver (specifically BAT), as well as provide mechanistic understanding of these changes.

Public Health Relevance

It has recently become apparent that brown adipose tissue (BAT) has a hitherto underappreciated effect on body temperature regulation (thermogenesis) in adult humans. We propose to test a hypothesis derived from our preliminary data that chronic alcohol consumption impairs the thermogenic capacity of BAT in mice, and that this impairment is associated with alcohol's effect on BAT vitamin A metabolism. This research will explore innovative concepts regarding alcohol's effect on BAT function, as well as alcohol's effect on vitamin A metabolism, and will provide an improved understanding of BAT's physiological function in the maintenance of body temperature, and the effect which alcohol has upon it.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA021336-02
Application #
8581336
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2012-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$171,000
Indirect Cost
$64,125
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Lee, Seung-Ah; Yuen, Jason J; Jiang, Hongfeng et al. (2016) Adipocyte-specific overexpression of retinol-binding protein 4 causes hepatic steatosis in mice. Hepatology 64:1534-1546
Brun, Pierre-Jacques; Wongsiriroj, Nuttaporn; Blaner, William S (2016) Retinoids in the pancreas. Hepatobiliary Surg Nutr 5:1-14
Clugston, Robin D; Huang, Li-Shin; Blaner, William S (2015) Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss. FASEB J 29:3654-67
Clugston, Robin D; Gao, Madeleine A; Blaner, William S (2015) The hepatic lipidome: a gateway to understanding the pathogenesis of alcohol-induced fatty liver. Curr Mol Pharmacol :
Yuen, Jason J; Lee, Seung-Ah; Jiang, Hongfeng et al. (2015) DGAT1-deficiency affects the cellular distribution of hepatic retinoid and attenuates the progression of CCl4-induced liver fibrosis. Hepatobiliary Surg Nutr 4:184-96
O'Mahony, Fiona; Wroblewski, Kevin; O'Byrne, Sheila M et al. (2015) Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein. Hepatology 62:615-26
Brun, Pierre-Jacques; Grijalva, Ambar; Rausch, Richard et al. (2015) Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and β-cell mass. FASEB J 29:671-83
Wang, Cynthia X; Jiang, Hongfeng; Yuen, Jason J et al. (2015) Actions of β-apo-carotenoids in differentiating cells: differential effects in P19 cells and 3T3-L1 adipocytes. Arch Biochem Biophys 572:2-10
Raghuvanshi, Shiva; Reed, Vanessa; Blaner, William S et al. (2015) Cellular localization of β-carotene 15,15' oxygenase-1 (BCO1) and β-carotene 9',10' oxygenase-2 (BCO2) in rat liver and intestine. Arch Biochem Biophys 572:19-27
Wongsiriroj, Nuttaporn; Blaner, William S (2015) The diversity of retinoid biology. Hepatobiliary Surg Nutr 4:220-1

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