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Inner workings of molecular thermostat point to pathways to fight diabetes, obesity
Date:9/11/2009

PHILADELPHIA Best known as the oxygen-carrying component of hemoglobin, the protein that makes blood red, heme also plays a role in chemical detoxification and energy metabolism within the cell. Heme levels are tightly maintained, and with good reason: Too little heme prevents cell growth and division; excessive amounts of heme are toxic.

Researchers at the University of Pennsylvania School of Medicine have discovered a molecular circuit involving heme that helps maintain proper metabolism in the body, providing new insights into metabolic disorders such as obesity and diabetes.

The work builds on 2007 findings from the same team, led by Mitchell Lazar, MD, PhD, Director of Penn's Institute for Diabetes, Obesity, and Metabolism, showing that a protein called Rev-erbα coordinates the daily cycles of heme. The new research, published online in Genes & Development, makes it clear that Rev-erbα, by controlling the production of heme, also plays a key role in maintaining the body's correct metabolism. This happens through a molecular pathway that allows the cell to monitor and adjust internal heme levels, creating more when heme levels fall, and slowing it down when levels rise.

The circuit is a negative feedback loop, with Rev-erbα as its central component, explains Lazar. "Rev-erbα is a thermostat for heme." When heme levels are high, Rev-erbα is activated, reducing heme, which leads the cell back towards a normal state. On the other hand, when heme levels are low, Rev-erbα activity is low, and this permits the cell to make more heme, again leading back toward a normal state. Maintaining this stasis allows energy metabolism to occur but avoids harm to the cell due to excessive levels of heme.

Understanding the control of heme levels is likely to be relevant to several diseases. For example, obesity is a condition where fat tissue builds up due to low energy expenditure relative to energy
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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