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Adropin treatment restores cardiac glucose oxidation in pre-diabetic obese mice

https://doi.org/10.1016/j.yjmcc.2019.02.012Get rights and content

Highlights

  • Long-term exposure to a high fat diet can promote metabolic dysfunction in the heart.

  • Adropin is a nutrient-responsive hormone shown to restore glucose oxidation in the skeletal muscle of diabetic mice.

  • We show that acute treatment of high fat diet-induced obese mice with adropin restores cardiac glucose oxidation in vivo.

  • Adropin improves pyruvate dehydrogenase activity in obese mice, which is linked to reduced inhibitory lysine acetylation.

Abstract

Exposure to a high fat (HF) diet promotes increased fatty acid uptake, fatty acid oxidation and lipid accumulation in the heart. These maladaptive changes impact cellular energy metabolism and may promote the development of cardiac dysfunction. Attempts to increase cardiac glucose utilization have been proposed as a way to reverse cardiomyopathy in obese and diabetic individuals. Adropin is a nutrient-regulated metabolic hormone shown to promote glucose oxidation over fatty acid oxidation in skeletal muscle homogenates in vitro. The focus of the current study was to investigate whether adropin can regulate substrate metabolism in the heart following prolonged exposure to a HF diet in vivo. Mice on a long-term HF diet received serial intraperitoneal injections of vehicle or adropin over three days. Cardiac glucose oxidation was significantly reduced in HF animals, which was rescued by acute adropin treatment. Significant decreases in cardiac pyruvate dehydrogenase activity were observed in HF animals, which were also reversed by adropin treatment. In contrast to previous studies, this change was unrelated to Pdk4 expression, which remained elevated in both vehicle- and adropin-treated HF mice. Instead, we show that adropin modulated the expression of the mitochondrial acetyltransferase enzyme GCN5L1, which altered the acetylation status and activity of fuel metabolism enzymes to favor glucose utilization. Our findings indicate that adropin exposure leads to increased cardiac glucose oxidation under HF conditions, and may provide a future therapeutic avenue in the treatment of diabetic cardiomyopathy.

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.

References (15)

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    Finally, previous studies in non-diabetic failing hearts have shown that blocking cardiac glucose uptake via insulin resistance may be cardioprotective, by preventing glucotoxicity from incomplete glucose metabolism (Taegtmeyer et al., 2013). While the short-term switch to increased glucose use driven by adropin treatment may potentiate such a response, this may be viewed as a less likely outcome, as glucose oxidation appears to be complete in both lean and obese mice after adropin treatment (Altamimi et al., 2019; Thapa et al., 2019). To address these questions, future work will need to focus on two main factors.

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