Working on genetically engineered obese mice with
seriously thickened hearts, a condition called 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, or
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 published in the March 6 issue of
the Proceedings of the National Academy of
"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," said
study senior author Joshua M. Hare, a professor and medical
director of the heart failure and cardiac transplantation
programs at the School of Medicine and its
Most obesity in people is associated with an inability
to use leptin made naturally in the body, said Hare, who
also is director of the cardiovascular section of Johns
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 said.
Hare and his colleagues tested the idea on mice with
left ventricular hypertrophy, or 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 said.
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 said, as people can develop antibodies
to CNTF. The scientists next plan to test CNTF in other
animal models of hypertrophy not related to obesity.
The study was supported by the Donald W. Reynolds
Foundation, the National Institutes of Health and the
Talles Family Fund for Cardiomyopathy Research. Co-authors
were Shubha V.Y. Raju, Meizi Zheng, Karl H. Schuleri,
Alexander C. Phan, Djahida Bedja, Roberto M. Saraiva, Omer
Yiginer, Koenraad Vandegaer, Kathleen L. Gabrielson, Dan E.
Berkowitz and Lili A. Barouch, all of Johns Hopkins; and
Christopher P. O'Donnell, of the University of Pittsburgh
School of Medicine.