Like sending a letter through the mail or a text over a cellular network, the heart can generate messages that travel long distances through the body.
Those messages ultimately reach fat cells, new research by scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) shows.
Prof. Koch was awarded a $1 million grant from the American Heart Association this week to explore the heart’s apparent ability to regulate the production of fat.
His lab found preliminary evidence for this odd phenomenon in mice two years ago, yet the exact mechanism remains unclear.
The key seems to be a gene that carries the recipe for an enzyme called GRK2, which is elevated in patients suffering from heart failure and has been the subject of Koch’s research for more than two decades.
When the Temple researchers inhibited the gene in mouse hearts, resulting in lower levels of that enzyme, the animals gained weight when fed a high-fat diet.
But when the researchers ramped up the gene’s activity, resulting in higher levels of the enzyme, mice given the same high-fat diet were somehow able to stay thin, Koch said.
“We found that the heart can talk to fat” in the lab mice, he said. “We know the heart is secreting something.”
The communication signal may be in the form of a hormone or some other type of chemical secretion, he said. Koch and his colleagues plan to use the grant to identify this signal from the heart, and then determine if it is present in people.
What that might mean for human health is unclear, but if the signal turns out to be a hormone, it would not be the only such agent secreted by the heart.
The heart also releases a hormone called BNP, which has been used to help diagnose heart failure – when the heart’s pumping action is too weak to keep up with the body’s demands, resulting in shortness of breath.
“The ability of the heart to communicate directly with fat had been suspected, but our study is the first to provide evidence of crosstalk between heart and fat tissue that is regulated by the enzyme, G protein-coupled receptor kinase 2 (GRK2),” said senior investigator Walter J. Koch, Ph.D., W.W. Smith Endowed Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, and Director of the Center for Translational Medicine at LKSOM.
The findings could have implications for modulating weight gain in patients with heart failure, a condition that arises when the heart can no longer effectively pump blood through the body.
In the breakthrough paper, published online in the journal JCI Insight, Dr. Koch and colleagues show that the heart relies on a cardiac-specific messenger, the signaling enzyme, GRK2, to relay information about metabolism to fat cells.
“GRK2 signaling in the heart effectively regulates fat accumulation in the body,” said Dr. Koch.
“Through this pathway, the heart ‘talks’ to fat and alters how fat responds to certain conditions.”
In previous work, Dr. Koch’s laboratory showed that GRK2 serves essential roles in both normal heart function and heart failure.
The researchers carried out their investigation in mice with GRK2 activity inhibited in the heart.
When fed a high fat diet, GRK2-inhibited mice accumulated significantly more fat than their littermates with normal GRK2 expression.
The experiment was repeated in mice with GRK2 overexpressed in the heart, mimicking the increase in GRK2 that occurs in heart failure in humans.
When given a high fat diet, these mice gained less body weight compared to their normal littermates.
Using complex metabolomics, a way of investigating metabolites associated with cellular processes, Dr. Koch’s team found that GRK2 signaling specifically altered branched chain amino acid (BCAA) and endocannabinoid metabolism in the heart.
GRK2-overexpressing mice on high fat diets had metabolite profiles that were distinct from those of GRK2-inhibited mice and normal animals.
“We also took the work a step further and identified one BCAA metabolite that enhanced fat cell differentiation in vitro,” Dr. Koch said. His team plans next to look for other metabolites and protein factors that are involved in crosstalk between the heart and fat tissue.
More information: Benjamin P. Woodall et al, Alteration of myocardial GRK2 produces a global metabolic phenotype, JCI Insight (2019). DOI: 10.1172/jci.insight.123848
Provided by Temple University
