Heart at center of systemic metabolism
MedWire News: Modulating a cardiac-specific thyroid hormone (TH) signaling pathway may have metabolic benefits for the whole body, researchers have found.
Eric Olson (University of Texas Southwestern Medical Center, Dallas, USA) and colleagues studied the heart-specific microRNA miR-208a, which acts to repress TH signaling via its target protein MED13.
As reported in Cell, the team aimed to assess the role of these molecules in the heart, but found that they had whole-body effects.
Mice on a high-fat diet increased their bodyweight by 75% over 6 weeks, but treatment with a miR-208a inhibitor reduced this increase to just 29%. Mice given the inhibitor had lower lipid levels than untreated mice, as well as less hepatic steatosis, lower insulin levels, and improved glucose tolerance.
Genetic overexpression of MED13 had similar effects, protecting mice against obesity and its metabolic consequences.
Mice overexpressing MED13 had higher oxygen consumption and carbon dioxide production, relative to weight-matched control mice, suggesting that the anti-obesity effect of MED13 overexpression was caused by increased systemic energy consumption.
MED13 is part of the Mediator complex, which regulates gene transcription through its action on nuclear hormone receptors. Consistent with this, the researchers found that 62 genes were downregulated in the hearts of mice overexpressing MED13, and many of these had a role in metabolism and were regulated by nuclear receptors.
Conversely, mice lacking functional MED13 were susceptible to diet-induced obesity, with Olson et al noting a slight increase in lean mass and a "dramatic" increase in fat mass in these mice relative to controls, after 6 weeks on a high-fat diet.
The benefits of miR-208a inhibition and MED13 overexpression in the mice are consistent with the recognized benefits of TH signaling. But the known drawbacks, such as tachycardia, arrhythmias, muscle wasting, and increased body temperature, did not occur in the mice.
"The target of anti-miR-208a is cardiac specific, thereby bypassing potential adverse effects on other tissues where TH exerts its effects," say the researchers.
"The apparent metabolic effects of miR-208a inhibition and MED13 elevation in the heart suggest that miR-208a inhibitors, in addition to providing benefit in the setting of cardiac dysfunction, may have therapeutic usefulness in a variety of metabolic disorders, such as obesity, hypercholesterolemia, type 2 diabetes, hepatic steatosis, and hyperlipidemia."
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By Eleanor McDermid