Insulin pulses keep the liver lean

July 19, 2005

Insulin, a hormone long recognized as a generator of fat, also keeps fat in the liver under control, according to a new study in the July issue of Cell Metabolism. The newly discovered role for insulin may explain how an organ frequently flooded with the fat-building hormone normally stays trim and also suggests new dietary strategies and treatments to avoid fatty liver, a growing healthcare epidemic, said the researchers.

Insulin produced by the pancreas allows cells to take up glucose from the bloodstream and burn it for energy. In the liver, insulin promotes the synthesis and storage of lipids and carbohydrates and blocks their breakdown and release into the bloodstream. A failure to make or respond to insulin in people with diabetes causes blood sugar levels to rise.

The current study uncovered a new mechanism whereby acute insulin pulses limit fat synthesis in the liver. This protective mechanism fails in obese mice and mice with persistently high levels of insulin, the researchers also found.

The findings suggest that periods of fasting between meals play a critical role in maintaining a lean and healthy liver by allowing insulin levels to rise and fall, said study lead author Sonia Najjar of the Medical University of Ohio.

Furthermore, she said, the results emphasize the central role of the liver in metabolic control. A liver overwhelmed with insulin--as can occur in those who overeat--may become resistant to the hormone, leading to greater fat production and visceral weight gain. Resulting hikes in blood sugar and fat can also spell diabetes and heart disease, Najjar added.

"When we eat, the pancreas produces insulin, which stimulates the absorption of sugar and fat by the liver," Najjar said. "But in today's Western society, large portions and frequent munching may lead insulin levels to remain high all the time. In that case, the liver no longer perceives pulses of the hormone and becomes resistant."

The researchers found that insulin pulses acutely reduce the activity of fat-building fatty acid synthase (FAS) in the liver by activating a second liver molecule, called CEACAM1. In mice lacking CEACAM1, insulin lost its ability to limit liver FAS activity. Obese mice and those with too much insulin also failed to exhibit a reduction in liver FAS activity following insulin delivery, suggesting that insulin's effects depend on prior levels of the hormone, the researchers reported.

"The current data demonstrate that CEACAM1 is at the intersection of the pathways regulating insulin and fat metabolism in liver," Najjar said.

"Although mutations in CEACAM1 have not been found in patients with diabetes or insulin resistance, it is tempting to speculate that CEACAM1-dependent inhibition of fatty acid synthesis might be compromised as a consequence or even a cause of the insulin-resistant state," wrote Alan Saltiel of the University of Michigan in an accompanying preview. In this case, he added, finding ways to mimic the effects of CEACAM1 might help to alleviate chronically elevated blood and liver lipids in patients with diabetes.
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The researchers include Sonia M. Najjar, Yan Yang, Mats A. Fernström, Sang-Jun Lee, Anthony M. DeAngelis, George A. Abou- Rjaily, Qusai Y. Al-Share, Tong Dai, Tiffany A. Miller, Shobha Ratnam, Randall J. Ruch, and Ana Maria Oyarce of the Medical University of Ohio, Toledo, Ohio; Stuart Smith of Children's Hospital Oakland Research Institute, Oakland, California; Sue-Hwa Lin of the University of Texas M.D. Anderson Cancer Center, Houston, Texas; Nicole Beauchemin of the McGill Cancer Center, McGill University, Montreal, Quebec, Canada. This work was supported by ADA research award and NIH grants, and by the Canadian Institutes for Health Research.

Najjar et al.: "Insulin acutely decreases hepatic fatty acid synthase activity." Publishing in Cell Metabolism, Vol. 2, July 2005, pages 43-53. DOI 10.1016/j.cmet.2005.06.001. www.cellmetabolism.org

Cell Press

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