Hypothalamic dysfunction as a key mechanism for alcoholic liver disease

Sandra Helinski

Christoph Buettner. Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029.

Hepatic steatosis is a key feature in alcoholic liver disease (ALD) and is also thought to represent an important pathophysiological step during ALD development. Insulin is a key regulator of metabolism and exerts some of its effect by signaling in the CNS, where it restrains hepatic glucose production and lipolysis in adipose tissue for example, the latter through dampening of sympathetic outflow to adipose tissue. Our laboratory has previously demonstrated that binge drinking impairs brain insulin action in rats, defined as the ability of brain insulin to suppress hepatic glucose production and white adipose tissue (WAT) lipolysis (Lindtner et al, SciTraMed, 2013). Preventing brain insulin resistance during binge drinking through the pharmacological inhibition of protein-tyrosine phosphatase 1β (PTP1β), a negative regulator of insulin signaling, prevented the glucose intolerance seen after binge drinking. Thus, we propose that alcohol binging impairs brain insulin action, which increases sympathetic outflow to WAT resulting in unrestrained lipolysis and hepatic steatosis. Here we present studies examining the role of adipose tissue lipolysis in alcohol induced adipose tissue inflammation and hepatic steatosis using both conditional knock out mouse models and pharmacological inhibition of lipolysis. These studies provide support for the paradigm that the brain-adipose axis plays an important role in ALD.