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Temporal Effects of Ethanol Consumption on Energy Homeostasis, Hepatic Steatosis, and Insulin Sensitivity in Mice

Authors

  • Rotonya M. Carr,

    1. Department of Medicine, Gastroenterology Division , Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Ravi Dhir,

    1. Institute for Diabetes, Obesity and Metabolism , Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Xiaoyan Yin,

    1. Institute for Diabetes, Obesity and Metabolism , Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Beamon Agarwal,

    1. Institute for Diabetes, Obesity and Metabolism , Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Rexford S. Ahima

    Corresponding author
    1. Institute for Diabetes, Obesity and Metabolism , Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    • Department of Medicine, Gastroenterology Division , Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Reprint requests: Rexford S. Ahima, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-104 Translational Research Center, 3400 Civic Center Blvd, Bldg. 421, Philadelphia, PA 19104; Tel.: 215-573-1875; Fax: 215-746-8931; E-mail: ahima@mail.med.upenn.edu

Abstract

Background

Alcoholic liver disease (ALD) progresses from steatosis to inflammation, fibrosis, and cirrhosis. Although ALD has been associated with insulin resistance, it is unclear whether insulin resistance coincides with the development of steatosis.

Methods

We studied the temporal relationship of steatosis and glucose homeostasis in mice fed a Lieber–DeCarli liquid control or ethanol (EtOH) diet for 2, 4, or 8 weeks. We studied the effects of alcohol consumption on energy balance, body composition, and hepatic lipids. Glucose tolerance test was performed, and insulin sensitivity was evaluated with hyperinsulinemic-euglycemic clamp.

Results

EtOH-fed mice developed hepatic steatosis over time as compared with control-fed mice despite similar energy intake and expenditure, and gain in body weight and fat. EtOH-fed mice developed glucose intolerance as early as 2 weeks, while insulin resistance developed at 4 weeks. A hyperinsulinemic clamp study at 8 weeks revealed both hepatic and peripheral insulin resistance in EtOH-fed mice. Insulin resistance was associated with hepatic steatosis, increased ceramide levels, and Perilipin 2 expression.

Conclusions

Chronic EtOH consumption leads to the development of hepatic steatosis, impaired glucose tolerance, and insulin resistance. These changes are independent of energy intake or expenditure, weight, whole body fat content, and inflammation. A better understanding of the processes linking EtOH-induced steatosis and abnormal glucose homeostasis may lead to novel therapies targeting the progression of ALD.

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