Cardiovascular PharmacologyStimulation of cardiac fatty acid oxidation by leptin is mediated by a nitric oxide–p38 MAPK-dependent mechanism
Introduction
Leptin is a peptide hormone secreted from adipose tissue whose levels are elevated in obesity (Flier, 1998). Since obesity is associated with cardiac dysfunction, there has been increasing interest in the physiological actions of leptin in the heart and the possible pathophysiological consequences of inadequate or excessive cardiac leptin signaling (Ren, 2004). An important injury produced in the heart by metabolic derangements is lipotoxicity, in which the cytoplasmic accumulation of fatty acid intermediates increases oxidative stress, resulting in the activation of pro-apoptotic, pro-fibrotic and pro-inflammatory pathways (Bielawska et al., 1997, Severson, 2004). Cytoplasmic accumulation of fatty acid intermediates is determined by the relative balance of fatty acid uptake and oxidation.
Acute leptin perfusion has previously been shown to stimulate fatty acid oxidation in the heart (Atkinson et al., 2002). Fatty acid entry to the mitochondria is controlled by carnitine palmitoyltransferase-1 (CPT-1), which is subject to inhibition by malonyl CoA. The kinase AMP-activated protein kinase (AMPK) is a known modulator of malonyl CoA levels, and is also stimulated by leptin in a range of tissues including the skeletal muscle. However, the stimulation of fatty acid oxidation in the heart was not AMPK or malonyl CoA-dependent (Atkinson et al., 2002) suggesting that other signaling pathways and targets are involved. Leptin has a negative inotopic effect in the heart which has been shown to be dependent on both nitric oxide and STAT-3-induced p38 mitogen activated protein kinase activation (p38 MAPK) (Nickola et al., 2000, Wold et al., 2002). We hypothesized that the same pathways may also be involved in the stimulation of fatty acid oxidation. Leptin has been shown to increase myocardial oxygen consumption (Atkinson et al., 2002), raising the possibility that it stimulates fatty acid oxidation by increasing uncoupling protein activity. The aim of the present study was to investigate whether the acute stimulation of fatty acid oxidation by leptin is mediated by nitric oxide and/or p38 MAPK, and to determine whether the effect is associated with the stimulation of mitochondrial fatty acid utilization or uncoupling activity.
Section snippets
Animals
Animals were cared for in accordance with the guidelines of the Canadian Council on Animal Care and the United States National Institute of Health Guide for the Care and Use of Laboratory Animals. Male Sprague–Dawley rats (weight matched 200–220 g) were purchased from Charles River Laboratories and allowed to acclimatize for 1 week. Following the acclimatization period, the rats were euthanized by 4% isofluorane anesthesia and excision of the hearts.
Measurement of cardiac function and metabolism
Measurement of cardiac function and
Results
Leptin produced a decrease in rate-pressure product, cardiac output and hydraulic power (Fig. 1). The decrease in rate-pressure product and cardiac output was attenuated to exactly the same degree by L-NAME and SB202190, but the decrease in hydraulic power was not attenuated due to a lack of effect of these inhibitors on developed pressure. AG490, by contrast, produced a recovery of function by the end of the perfusion period, although the initial fall in function was either unchanged or, in
Discussion
Leptin has previously been shown to acutely stimulate fatty acid oxidation independent of AMPK. Although studies in isolated cardiomyocytes have suggested a role for AMPK in this response (Palanivel et al., 2006), we observed a stimulation of fatty acid oxidation which was independent of AMPK and CPT-1. These data agree with previous studies in the intact heart (Atkinson et al., 2002), suggesting that the presence of other cell types in the cardiac syncytium may ameliorate the AMPK-dependent
Acknowledgments
We thank Hannah Parsons for her assistance with preliminary experiments for mitochondrial function measurements, and Violet Yuen for valuable assistance in the preparation of this manuscript. This work was supported by a grant from the Canadian Institutes of Health Research. S.M. was a recipient of a Postdoctoral Fellowship from The Higher Education Commission of Pakistan. N.P. was a visiting pharmacy honour student from the School of Pharmacy at the University of London.
References (18)
- et al.
Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis
J. Biol. Chem.
(2002) - et al.
Cyclic GMP-dependent and -independent regulation of MAP kinases by sodium nitroprusside in isolated cardiomyocytes
Biochim. Biophys. Acta
(2000) - et al.
Distinct effects of short- and long-term leptin treatment on glucose and fatty acid uptake and metabolism in HL-1 cardiomyocytes
Metabolism
(2006) - et al.
Sodium nitroprusside activates p38 mitogen activated protein kinase through a cGMP/PKG independent mechanism
Life Sci.
(2007) - et al.
Preconditioning enhanced glucose uptake is mediated by p38 MAP kinase not by phosphatidylinositol 3-kinase
J. Biol. Chem.
(2000) - et al.
Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts
Am. J. Physiol.
(1994) - et al.
AMPK and metabolic adaptation by the heart to pressure overload
Am. J. Physiol. Heart Circ. Physiol.
(2007) - et al.
Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway
Nat. Cell Biol.
(2004) - et al.
Measurements of energy metabolism in the isolated heart
Cited by (35)
Modulation of the transcriptomic profile of the R2C tumor Leydig cell line by the adipose tissue derived hormone leptin
2018, Reproductive BiologyCitation Excerpt :Testicular action of leptin may depend on Lepr-b, being responsible for most of Lepr activity, as it was detected within the mouse testis at all developmental stages, and its expression was increased at adulthood (26 and 52 weeks) and within adult Leydig cells [6]. Activation of Lepr-b by leptin modulates a cascade of intracellular signal transduction pathways, including the Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) [7], phosphoinositide 3-kinase (PI3K) [8], 5′-AMP-activated protein kinase (AMPK) [9,10] and MAPK pathways such as extracellular signal-related kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases (JNK), and p38 [11,12]. Modulation of these signaling pathways may lead to regulation of different target genes having influences on steroidogenesis and Leydig cells’ function.
Insect cytokine paralytic peptide activates innate immunity via nitric oxide production in the silkworm Bombyx mori
2013, Developmental and Comparative ImmunologyCitation Excerpt :We recently demonstrated that active PP acutely induced p38 MAPK activation in the silkworm fat body, and that the reaction was required for PP-dependent AMP gene expression in the fat body (Ishii et al., 2010b). Although studies of the relationship between NO and p38 MAPK are relatively scarce, Sharma et al. reported that leptin, a peptide hormone, induced p38 MAPK activation via NO production in rat cardiac cells (Sharma et al., 2009). Here, we found that PP-dependent p38 MAPK phosphorylation was suppressed by l-NAME and that an NO donor induced p38 activation in the silkworm fat body.
Implications of leptin in neuroendocrine regulation of male reproduction
2013, Reproductive BiologyCitation Excerpt :Leptin receptor signaling in peripheral tissues is not well understood but involves members of the STAT family of transcription factors. Activation of Ob-Rb by leptin sets off a cascade of intracellular signal transduction pathways in male rodents, including the Janus kinase 2 (JAK2)/STAT3 [45], PI3K [46], 5′-AMP-activated protein kinase (AMPK) [47,48] and MAPK pathways such as extracellular signal-related kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases (JNK), and p38 [49,50]. For the JAK2/STAT3 pathway, leptin-induced clustering of Ob-Rb activates JAK2 [51].
Is there NO help for leptin?
2012, BiochimieCitation Excerpt :Other studies have demonstrated that leptin enhances NO production and lipid catabolism in the human placenta, which provides supportive evidence for its role in placental functions [85]. In addition, leptin stimulates fatty acid oxidation in the intact heart by a STAT-3–NO–p38 MAPK-dependent mechanism [86]. There is now clear evidence that leptin acts via NO production in multiple tissues.
Adenosine-mediated inhibition of 5'-AMP-activated protein kinase and p38 mitogen-activated protein kinase during reperfusion enhances recovery of left ventricular mechanical function
2012, Journal of Molecular and Cellular CardiologyCitation Excerpt :This study tested the hypothesis that ADO-mediated attenuation of glycolysis is due to reduced AMPK-mediated PFK-2 phosphorylation and subsequent inhibition of PFK-1 activity. Another stress-responsive protein kinase activated by ischemia is p38 mitogen activated protein kinase (MAPK) [14] and it has similar actions as AMPK on myocardial glucose uptake [15] and fatty acid oxidation [16], but the role of p38 MAPK in the regulation of myocardial glycolysis during reperfusion has not yet been determined. The activities of AMPK and p38 MAPK are influenced by the extent of phosphorylation, and their regulation by their respective upstream kinases has been well characterized [17,18].
Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin
2024, International Journal of Molecular Sciences