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Discovery explains how cellular pathways converge to regulate food intake and body weight
Date:7/3/2012

BOSTON -- In the complex chain of molecular events that underlie eating behaviors and body weight, the AMP-activated protein kinase (AMPK) enzyme has proven to be a critical link.

Now, researchers at Beth Israel Deaconess Medical Center (BIDMC) have identified the mechanism responsible for inhibition of AMPK activity in the hypothalamus, a discovery that not only provides a deeper understanding of energy balance but also reveals a critical integration point where multiple signaling pathways, including PI3K-AKT and mTOR converge.

Described in the July 3 issue of Cell Metabolism, the findings could yield new opportunities for the development of treatments for both metabolic diseases and cancer.

"AMPK is an evolutionarily conserved 'fuel gauge,'" says senior author Barbara Kahn, MD, a scientist in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and the George Richards Minot Professor of Medicine at Harvard Medical School. Activated when cellular energy supplies are low, AMPK also functions at the whole body level to regulate metabolism and energy balance.

The Kahn laboratory was the first to describe AMPK's critical role in mediating the actions of leptin, the hormone produced by fat cells that serves as a master regulator of neuroendocrine, metabolic, vascular, sympathetic and immune function. In 2002, Kahn demonstrated that AMPK is activated by leptin in skeletal muscle, thereby enabling the hormone to metabolize fatty acids. Subsequently, in 2004, her laboratory discovered that an opposing scenario takes place in the brain's hypothalamus, where AMPK is inhibited by leptin.

"Having determined that leptin's effects on food intake and body weight depend on the inhibition of AMPK in the hypothalamus, we wanted to determine the signaling events that were responsible for this effect," she explains.

The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in
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Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

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