Short communicationAdropin treatment restores cardiac glucose oxidation in pre-diabetic obese mice
Graphical abstract
Introduction
Cardiac mitochondria supply around 90% of the energy required for contractile function via oxidative phosphorylation. Under normal conditions, most of this energy is generated from the oxidation of fatty acids, with the remainder coming from alternative sources such as glucose, lactate and ketones [1]. While hearts have a clear preference for fatty acids under normal conditions, they maintain a level of fuel substrate flexibility to continue contractile function under stress. This flexibility is lost in disease states such as diabetic cardiomyopathy, where increased plasma fatty acid levels and decreased glucose uptake can lead to an over-reliance on fatty acid oxidation for ATP generation. This results in decreased cardiac energy efficiency, which may exacerbate the bioenergetic deficits that characterize metabolic disease states [2].
To repair the metabolic dysfunction found in cardiovascular diseases, one pathway of research has focused on the pharmacological inhibition of cardiac fatty acid oxidation to promote glucose utilization (a more efficient fuel in terms of energy produced per mole of oxygen used [2]). These studies resulted in the development of several drugs (e.g. etomoxir, perhexiline, trimetazidine) that showed great therapeutic potential, but have had limited clinical success due to off-target metabolic effects [3]. Alternative strategies to promote a switch from fatty acid to glucose utilization in the diabetic heart have therefore been sought.
Adropin is a liver- and brain-derived peptide shown to reduce insulin resistance in mice subject to diet-induced obesity [4]. Recent work has demonstrated that adropin can promote the use of glucose as an oxidation substrate in skeletal muscle homogenates isolated from diabetic animals, driven by changes in the expression of fatty acid oxidation and glucose utilization genes [5,6]. However, it remained unclear from these studies if adropin would produce these potentially beneficial effects in vivo. As such, in this study we sought to investigate if adropin could perform a similar function and restore glucose oxidation in the hearts of pre-diabetic obese mice.
Section snippets
Materials and methods
Detailed methods are available in the attached supplemental material.
Adropin treatment restores cardiac glucose oxidation in obese mice
Mice placed on a long-term, high fat (HF) diet develop changes in cardiac metabolism, which results in increased fatty acid uptake, cardiomyocyte lipid accumulation, and contractile dysfunction [7]. We sought to determine whether glucose oxidation is modulated by adropin treatment in this murine model of cardiac metabolic dysfunction. Age- and weight-matched mice on a 20-week HF diet received five serial intraperitoneal injections of vehicle (saline) or adropin (450 nmol/kg) over three days, as
Discussion
In this study, we show for the first time that adropin can regulate fuel substrate utilization in vivo. Treatment of obese, pre-diabetic mice with adropin restored relative cardiac glucose oxidation rates to those seen in lean animals, significantly reversing the metabolic dysfunction observed in vehicle-treated high fat diet animals. Unlike previous studies in skeletal muscle, the ability of adropin to promote glucose oxidation was independent of the inhibitory effect of PDK4 on pyruvate
Funding
This work was supported by an American Heart Association Postdoctoral Fellowship (17POST33670489) to D.T.; by National Institutes of Health T32 Fellowships (T32HL110849) to J.R.M. and (T32DK007052) to L.R.E.; by National Institutes of Health grants (R01DK114012 and R01DK119627) to M.J.J.; National Institutes of Health grants (K22HL116728, R56HL132917 and R01HL132917) to I.S.; by a University of Pittsburgh HVI-VMI Innovator Award to I.S.; and by an American Diabetes Association Innovative Basic
Acknowledgments
Adropin was synthesized by the University of Pittsburgh Peptide and Peptoid Synthesis Core. Due to space restrictions, we could not reference the important work of several groups in this field. We apologize to the authors of these works for any omissions.
Conflicts of interest
None.
Author contributions
D.T., B.X., M.Z., M.W.S., J.R.M., B.R.H, L.R.E and S.J.M. performed experiments. M.J.J. and I.S. conceived the study and designed experiments. D.T., B.X., M.J.J. and I.S. analyzed data. C.F.M and S.G.W. provided critical input and expertise. D.T., M.J.J. and I.S. produced fig. S.G.W., M.J.J. and I.S. wrote the manuscript.
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