Central Leptin Signaling Is Required to Normalize Myocardial Fatty Acid Oxidation Rates in Caloric-Restricted <i>ob/ob</i> Mice

Sloan, Crystal; Tuinei, Joseph; Nemetz, Katherine; Frandsen, Jonathan; Soto, Jamie; Wride, Noah; Sempokuya, Tomoki; Alegria, Luis; Bugger, Heiko; Abel, E. Dale

doi:10.2337/db10-1106

Cited by 80 publications

(70 citation statements)

References 29 publications

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“…Electron micrographs from 12-week-old Lep ob mice revealed disordered cristae (44). However, no noticeable changes in cristae density were observed in Lep ob mice at 4-5 weeks of age, indicating a gradual structural distortion over time (144).…”

Section: Mitochondrial Morphology and Function In Dcm Patientsmentioning

confidence: 82%

Mitochondrial Dynamics in Diabetic Cardiomyopathy

Galloway

Yoon

2015

Antioxidants & Redox Signaling

102

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Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca 2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545Signal. 22, -1562

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Section: Mitochondrial Morphology and Function In Dcm Patientsmentioning

confidence: 82%

Mitochondrial Dynamics in Diabetic Cardiomyopathy

Galloway

Yoon

2015

Antioxidants & Redox Signaling

102

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“…Pathological conditions can also be accompanied by alterations in cardiac substrate use; however, it remains unclear as to whether the shift in energy substrate is a cause or consequence of the pathological insult. Metabolic heart disease causes an increase in FA oxidation,6, 7, 8, 9 whereas increased glucose use is observed under conditions that induce pathological hypertrophy, myocardial ischemia, or heart failure 10. Analyses of some mouse models suggest that ventricular hypertrophy precedes the metabolic changes that result in reduced cardiac FA oxidation and increased glucose use 11, 12.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Transition From Decompensated to Pathological Hypertrophy

Pascual

Schisler

Grevengoed

et al. 2018

JAHA

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BackgroundLong‐chain acyl‐CoA synthetases (ACSL) catalyze the conversion of long‐chain fatty acids to fatty acyl‐CoAs. Cardiac‐specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1‐mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function.Methods and ResultsGlobal cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H−/− hearts 2 weeks after Acsl1 ablation. Comparison of the 2‐ and 10‐week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint.ConclusionsShort‐term cardiac‐specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart‐specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy.

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“…In addition, Ob mice heart rapidly modifies its energy metabolism, resulting in augmented fatty acid and decreased glucose consumption. 20 Thus, it remains to be elucidated whether our finding that Ob mice are resistant to atrial fibrosis by continuous AngII infusion is attributable to the direct effects of leptin or attributable to indirect metabolic changes characteristic to the mice. 21 On the other hand, leptin has been shown to regulate systemic immune responses, which may explain the lack of fibrotic responses to AngII in Ob mice and Zucker rat atrial fibroblasts.…”

Section: Circ Arrhythm Electrophysiol April 2013mentioning

confidence: 99%

Role of Leptin Signaling in the Pathogenesis of Angiotensin II–Mediated Atrial Fibrosis and Fibrillation

Fukui

Takahashi

Nakada

et al. 2013

Circ: Arrhythmia and Electrophysiology

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The online-only Data Supplement is available at http://circep.ahajournals.org/lookup/suppl/doi:10.1161/CIRCEP.111.000104/-/DC1. Correspondence to Naohiko Takahashi, MD, PhD, Department of Laboratory Examination and Diagnostics, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail takanao@oita-u.ac.jp Background-We examined the hypothesis that leptin signaling contributes to the atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin II (AngII). Methods and Results-Eight-week-old male CL57/B6 (CNT) and leptin-deficient ob/ob mice (Ob) were subcutaneously infused with AngII (2.0 mg/kg per day). Two weeks later, transesophageal burst pacing and an electrophysiological study using isolated perfused hearts were performed. Left-atrial tissues were collected to determine interstitial fibrosis by Masson trichrome staining, and the expressions of mRNAs related to inflammatory profibrotic signals were assessed. Left-atrial fibroblasts were isolated from adult Sprague-Dawley and Zucker rats. The effects of leptin (100 ng/mL) or AngII (100 nmol/L) treatment were evaluated. In CNT-AngII mice, leptin expression in the left atrium was upregulated (P<0.01).Transesophageal burst pacing induced atrial fibrillation in 88% (7/8) of CNT-AngII mice, but not in Ob-AngII mice (0/8; P<0.01). In isolated perfused hearts, atrial fibrillation was induced only in CNT-AngII mice (4/6; 67%). Interatrial conduction time was prolonged in CNT-AngII mice (P<0.01), but not in Ob-AngII mice. The upregulation of collagen 1, collagen 3, transforming growth factor-β1, α-smooth muscle actin, MCP-1, F4/80, and RANTES mRNA, which was seen in CNT-AngII mice, was attenuated in Ob-AngII mice. In cultured Sprague-Dawley rat atrial fibroblasts, AngII treatment increased leptin expression (P<0.01). Addition of leptin increased transforming growth factor-β1, α-smooth muscle actin, MCP-1, and RANTES expressions in Sprague-Dawley rat atrial fibroblasts, but not in Zucker rat atrial fibroblasts. Conclusions-Our Fukui et al Leptin and Atrial Fibrillation 403in rat atrial fibroblasts that contain a malfunctioning receptor for leptin receptor (the Zucker rat model). MethodsAll experimental procedures were conducted in accordance with the guidelines of the Physiological Society of Oita University, Japan, for the care and use of laboratory animals, following the guidelines established by the US National Institutes of Health. For detailed Methods, see the online-only Data Supplement. Results Hemodynamic CharacteristicsSystolic blood pressure and heart rate measurements during the experimental period are shown in Figure I in the onlineonly Data Supplement. Before AngII infusion, no significant differences in these 2 parameters were observed between control (CNT) and Ob mice. Continuous AngII infusion caused elevation of systolic blood pressure and heart rate in both CNT-AngII and Ob-AngII mice (both P<0.01). We observed no significant differences in these 2 parameters between CNTAngII mice and Ob-AngII mice on days 7 and ...

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Central Leptin Signaling Is Required to Normalize Myocardial Fatty Acid Oxidation Rates in Caloric-Restricted ob/ob Mice

Cited by 80 publications

References 29 publications

Mitochondrial Dynamics in Diabetic Cardiomyopathy

Mitochondrial Dynamics in Diabetic Cardiomyopathy

Modeling the Transition From Decompensated to Pathological Hypertrophy

Role of Leptin Signaling in the Pathogenesis of Angiotensin II–Mediated Atrial Fibrosis and Fibrillation

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