Abstract
The heart requires a continuous supply of energy but has little capacity for energy storage and thus relies on exogenous metabolic sources. We previously showed that cardiac MED13 modulates systemic energy homeostasis in mice. Here, we sought to define the extra-cardiac tissue(s) that respond to cardiac MED13 signaling. We show that cardiac overexpression of MED13 in transgenic (MED13cTg) mice confers a lean phenotype that is associated with increased lipid uptake, beta-oxidation and mitochondrial content in white adipose tissue (WAT) and liver. Cardiac expression of MED13 decreases metabolic gene expression in the heart but enhances them in WAT. Although exhibiting increased energy expenditure in the fed state, MED13cTg mice metabolically adapt to fasting. Furthermore, MED13cTg hearts oxidize fuel that is readily available, rendering them more efficient in the fed state. Parabiosis experiments in which circulations of wild-type and MED13cTg mice are joined, reveal that circulating factor(s) in MED13cTg mice promote enhanced metabolism and leanness. These findings demonstrate that MED13 acts within the heart to promote systemic energy expenditure in extra-cardiac energy depots and point to an unexplored metabolic communication system between the heart and other tissues.See also: M Nakamura & J Sadoshima (December 2014)
Highlights
Obesity has reached epidemic proportions worldwide and is associated with increased risk of cardiovascular disease, hypertension, and diabetes, resulting in enhanced morbidity and mortality (Van Gaal et al, 2006)
In the fed state, metabolic gene expression is decreased in MED13cTg hearts, long-chain fatty acid utilization is decreased, and there is a decrease in accumulation of intermediates of fatty acid metabolism
The results of this study demonstrate that elevation of MED13 expression in the mouse heart enhances metabolic rates and mitochondrial content of white adipose tissue (WAT) and liver, resulting in a lean phenotype, with distinct changes in metabolic profile that are most pronounced in the fed state
Summary
Obesity has reached epidemic proportions worldwide and is associated with increased risk of cardiovascular disease, hypertension, and diabetes, resulting in enhanced morbidity and mortality (Van Gaal et al, 2006). Obesity is associated with a variety of abnormalities in metabolic homeostasis, including insulin resistance, glucose intolerance, hyperlipidemia, and a condition described as “metabolic inflexibility”, referring to impairment in normal switching from fatty acid to glucose utilization in the fasted to fed transition (Storlien et al, 2004; Harmancey et al, 2008). The ability of the body to adapt to metabolic changes in both the fed and fasted states requires inter-organ communication. The heart is interesting with respect to inter-organ metabolic signaling because it requires a continual supply of energy to sustain contraction and metabolism, but stores only enough energy for a few heart beats. The heart relies primarily on oxidation of fatty acids delivered via the circulation for energy
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