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Johns Hopkins scientists exploit novel route to reverse enlarged hearts in obese mice


Nerve growth factor makes end run around leptin, a brain hormone linked to appetite regulation

Working on genetically engineered obese mice with seriously thickened hearts, a condition call cardiac hypertrophy, scientists at Johns Hopkins have used a nerve protection and growth factor on the heart to mimic the activity of the brain hormone leptin, dramatically reducing the size of the heart muscle.

Leptin is a protein hormone made by fat cells that signals the brain to stop eating. Alterations in the leptin-making gene may create leptin deficiency linked to obesity and other defects in weight regulation.

By injecting so-called ciliary neurotrophic factor (CNTF) into mice that were either deficient in or resistant to leptin, the researchers reduced the animals’ diseased and thickened heart muscle walls by as much as a third and the overall size of the left ventricle, the main pumping chamber, up to 41 percent, restoring the heart’s architecture toward normal.

Enlarged hearts lead to heart failure and death. Results of the study, supported in part by the National Institutes of Health, are to be published in the March 6 issue of the Proceedings of the National Academy of Sciences.

"These findings suggest there’s a novel brain-signaling pathway in obesity-related heart failure and have therapeutic implications for patients with some forms of obesity-related cardiovascular disease," says study senior author Joshua M. Hare, M.D., a professor and medical director of the heart failure and cardiac transplantation programs at The Johns Hopkins University School of Medicine and its Heart Institute.

Most obesity in people is associated with an inability to use leptin made naturally in the body, says Hare, who also is director of the cardiovascular section of Hopkins’ Institute for Cellular Engineering.

"We knew that leptin supplements wouldn’t address obesity-linked heart disease, but reasoned that CNTF might be a way to get around leptin resistance by activating a related signaling pathway with similar effects on body weight and metabolism," he says.

Hare and his colleagues tested the idea on mice with left ventricular hypertrophy (LVH), a condition in which the left ventricle expands and stiffens, preventing proper blood flow to the body. In humans, obesity is a major risk factor for LVH, which results from stress on the heart. As the heart muscle is worked harder, it bulks up.

"Our finding that CNTF causes LVH to regress not only in leptin-deficient animals but also in those lacking a functional leptin receptor establishes the existence of a new pathway to help regulate LVH," Hare says.

For the study, Hare and colleagues first examined whether CNTF receptors were present and functional in the heart muscles by staining heart muscle cells with a chemical that would highlight the receptors when viewed under a high-powered microscope. These tests showed that CNTF receptors were located on the cells’ surfaces.

Next, they randomly assigned a set of leptin-deficient mice into three groups: a third received daily abdominal injections of CNTF, a third were fed a calorie-restricted diet, and a third ate as much as they wanted. The researchers used the same three approaches plus leptin supplements on another group of leptin-resistant mice.

Ultrasound exams of the hearts after four weeks showed that CNTF decreased the thickness of the wall dividing the heart chambers by as much as 27 percent, decreased the thickness of the wall at the back of the heart by as much as 29 percent and overall volume of the left ventricle by as much as 41 percent. As expected, leptin supplements did not change left ventricular wall thickness.

CNTF-treated mice also showed reduced heart-cell width, a direct measure of the amount of hypertrophy.

More research is to be done before CNTF can be used to treat patients, Hare says, as people can develop antibodies to CNTF. The scientists next plan to test CNTF in other animal models of hypertrophy not related to obesity.

David March | EurekAlert!
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