leptin and Cardiomegaly

Leptin is a 16 kDa peptide that was first identified in 1994 through positional cloning of the mouse obesity gene. Although the primary function of leptin is to act a satiety factor through its actions on the hypothalamus, it is now widely recognized that leptin can exert effects on many other organs through activation of its receptors, which are ubiquitously expressed. Leptin is secreted primarily by white adipocytes, but it is also produced by other tissues including the heart where it can exert effects in an autocrine or paracrine manner. One of these effects involves the induction of cardiomyocyte hypertrophy, which appears to occur via multiple cell signalling mechanisms. As adipocytes are the primary site of leptin production, plasma leptin concentrations are generally positively related with body mass index and the degree of adiposity. However, hyperleptinemia is also associated with cardiovascular disease, including heart failure, in the absence of obesity. Here we review the potential role of leptin in heart disease, particularly pertaining to its potential contribution to myocardial remodelling and heart failure, as well as the underlying mechanisms. We further discuss potential interactions between leptin and another adipokine, adiponectin, and the potential implications of this interaction in terms of fully understanding leptin's effects.

Topics: Adiponectin; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Body Composition; Calcineurin; Cardiomegaly; Heart Failure; Humans; Leptin; Mitochondria, Heart; Probiotics; Proteins; Receptors, Leptin; rho-Associated Kinases; Signal Transduction

1. Leptin is a 16-kDa hormone, synthesized primarily by adipocyte, which acts as a key factor for maintenance of energy homeostasis in central and peripheral tissues. In most obese individuals, serum leptin levels are increased and correlate with the individual's body mass index. 2. Abundant investigations ranging from clinical and animal model studies to in vitro analyses show that leptin plays a pivotal role in obesity-related cardiovascular diseases (CVD). Hyperleptinaemia has been confirmed to be a predictor of acute cardiovascular events. However, some studies have shown that leptin has a cardioprotective effect in leptin-deficient models. These data suggest the influences of leptin on the pathophysiology of cardiovascular diseases are complex and not completely understood. 3. In the present review, we summarize the major leptin signalling pathways, including Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT), mitogen-activated protein kinases (MAPK), and phosphatidylinositol 3-kinase (PI-3K) signalling pathways, and analyse the probable mechanisms of selective leptin resistance. We then provide a detailed review of the effects of leptin on the cardiovascular system, including sympathoactivation, oxidative stress, vascular inflammation, endothelial dysfunction, vascular cell proliferation, cardiomyocytes hypertrophy, as well as fatty acid metabolism, all of which contribute to the pathogenesis of cardiovascular diseases (e.g. ischaemic heart disease). The central premise of this review is to elucidate the mechanisms by which leptin affects the cardiovascular function and provide insight into obesity-related CVD.

Topics: Animals; Cardiomegaly; Cardiovascular Diseases; Endothelium, Vascular; Extracellular Matrix; Female; Humans; Inflammation; Leptin; Male; Mice; Myocardium; Obesity; Rats; Receptors, Leptin; Risk Factors; Signal Transduction; Thrombosis

Perilipin 5 (Plin5) is well known to maintain the stability of intracellular lipid droplets (LDs) and regulate fatty acid metabolism in oxidative tissues. It is highly expressed in the heart, but its roles have yet to be fully elucidated.. Plin5-deficient mice and Plin5/leptin-double-knockout mice were produced, and their histological structures and myocardial functions were observed. Critical proteins related to fatty acid and glucose metabolism were measured in heart tissues, neonatal mouse cardiomyocytes and Plin5-overexpressing H9C2 cells. 2-NBDG was employed to detect glucose uptake. The mitochondria and lipid contents were observed by MitoTracker and BODIPY 493/503 staining in neonatal mouse cardiomyocytes.. Plin5 deficiency impaired glucose utilization and caused insulin resistance in mouse cardiomyocytes, particularly in the presence of fatty acids (FAs). Additionally, Plin5 deficiency increased the NADH content and elevated the expression of lactate dehydrogenase (LDHA) in cardiomyocytes, which resulted in increased lactate production. Moreover, when fatty acid oxidation was blocked by etomoxir or LDHA was inhibited by GSK2837808A in Plin5-deficient cardiomyocytes, glucose utilization was improved. Leptin-deficient mice exhibited myocardial hypertrophy, insulin resistance and altered substrate utilization, and Plin5 deficiency exacerbated myocardial hypertrophy in leptin-deficient mice.. Our results demonstrated that Plin5 plays a critical role in coordinating fatty acid and glucose oxidation in cardiomyocytes, providing a potential target for the treatment of metabolic disorders in the heart.

Topics: Animals; Cardiomegaly; Fatty Acids; Glucose; Insulin Resistance; Lactic Acid; Leptin; Mice; Perilipin-5

Cardiovascular disease in obese individuals with type 2 diabetes is often associated with hyperleptinemia and leptin resistance, while other studies support that leptin has cardioprotective effects. Besides, the role of leptin in regulating cardiac atrophy or hypertrophy remains to be clearly defined. In fact, in rats with normal leptin sensitivity, the molecular underpinnings of the effects of central leptin regulating cardiac structural pathways remain poorly understood.. Hence, we assessed the effects of intracerebroventricular (icv) leptin infusion on cardiac remodeling analyzing FOXO1/3 and mTORC1 pathways, focusing special attention to PPARβ/δ as mediator of central leptin's effects on cardiac metabolism.. Male 3-months-old Wistar rats, infused with icv leptin (0.2 μg/day) for 7 days, were daily co-treated intraperitoneally with the specific PPARβ/δ antagonist GSK0660, at 1 mg/kg per day along leptin treatment.. Central leptin regulated dynamically, in an opposite manner, the network between FOXOs and mTORC1 and induced an atrophy-related gene program in cardiac tissue. Leptin activated the anti-hypertrophic kinase GSK3β and increased the protein levels of muscle-specific ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/Atrogin-1 involved in limiting cardiac hypertrophy. FOXO1 activity and the expression of their target genes, Sod2 and Lpl, were also increased in the heart upon central leptin infusion. Besides, Beclin-1 and LC3B-II, gene products of the autophagic pathway response, were upregulated, while the content and expression levels of phenotypic markers of cardiac hypertrophy as ANP and β-myosin heavy chain, gene product of Myh7 were significantly decreased. On the other hand, mTORC1 activity and OXPHOS protein levels were decreased suggesting a key role of central leptin preventing cardiac oxidative stress. In fact, the content of carbonylated proteins, TBARS and ROS/RSN were not increased in cardiac tissue in response to central leptin infusion. Finally, the pharmacological inhibition of PPARβ/δ, via in vivo administration of the selective antagonist GSK0660, blunted the induction of FOXO1/3, Atrogin-1, MuRF1 and GSK3β in the heart mediated by icv leptin infusion.. Our results demonstrate that, in lean rats with normal leptin sensitivity, central leptin regulates nutrient sensing pathways in heart contributing to balance cardiac remodeling through the anti- and pro-hypertrophic programs, and in this process is involved PPARβ/δ.

Topics: Animals; Cardiomegaly; Forkhead Box Protein O1; Forkhead Box Protein O3; Heart; Leptin; Male; Myocardium; PPAR delta; PPAR-beta; Rats; Rats, Wistar; Reactive Nitrogen Species; Reactive Oxygen Species; Signal Transduction; Sulfones; Thiophenes; TOR Serine-Threonine Kinases; Ventricular Remodeling

Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia.. Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy.. Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance.. In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ± 3.0, 6.5 ± 1.6, 6.5 ± 1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ± 1.7, 9.1 ± 1.3, 8.3 ± 1.7 mm, P < .01), and LV mass (140.7 ± 45.9, 128.7 ± 37.9, 110.9 ± 29.1 g, P < .01), and increased septal e' velocity (8.6 ± 1.7, 10.0 ± 2.1, 10.7 ± 2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD.. Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

Topics: Adolescent; Adult; Blood Pressure; Cardiomegaly; Echocardiography; Female; Glycated Hemoglobin; Humans; Hypertrophy, Left Ventricular; Insulin Resistance; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; Male; Middle Aged; National Institutes of Health (U.S.); Prospective Studies; Triglycerides; United States; Ventricular Septum; Young Adult

The consumption of high calorie-content diets is the first cause of obesity, probably the main health issue worldwide; however, the experimental evidences for evaluating the differential metabolic modifications of high-sucrose or high-fat diets are scare. We evaluated the metabolic outcomes of the obesity induced by the chronic consumption of high-sucrose (HS), high-fat (HF) or combined diets (HSHF), among the effect on the development of cardiac hypertrophy in Wistar rats. Rats from the HS, HF, and HSHS groups developed moderate obesity. Only the HS group showed increased triglycerides levels after four months. Increased leptin levels were observed in HS and HF groups without changes on cardiac hypertrophy; on the opposing, HSHF group presented hypertrophy without the changes in serum leptin. The three experimental groups showed a decreased expression of leptin receptors ObR-b. In our results, the kind of diet for the induction of obesity is relevant for the outcome of the pathological profile.

Topics: Adipose Tissue; Animals; Cardiomegaly; Diet, High-Fat; Dietary Sugars; Energy Intake; Fructose; Leptin; Male; Obesity; Overweight; Rats; Rats, Wistar; Risk Factors; Triglycerides

Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.

Topics: Animals; Cardiomegaly; Diet, High-Fat; Glucose Intolerance; Hypercholesterolemia; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Obesity; Receptor, Angiotensin, Type 2

Over a third of reproductive-age women in the USA are obese, and the prevalence of cardiovascular disease (CVD) is rising in premenopausal women. Cardiac hypertrophy is an independent predictor of CVD. In contrast to pregnancy, where transiently increased left ventricular (LV) mass is not associated with cardiac damage, obesity-mediated cardiac hypertrophy is pathological. There is a paucity of data describing the effect of obesity during pregnancy on maternal cardiovascular health. The purpose of this study was to determine the long-term effect of obesity during pregnancy on cardiac function and structure in mice.. Female C57BL/6 J mice were fed a high-fat (HF) or a low-fat (LF) diet for 20 weeks. After 4 weeks, LF- and HF-fed female mice were either crossed with males to become pregnant or remained non-pregnant controls. Following delivery, pups were euthanized, and females maintained on respective diets. After 20 weeks of diet feeding, cardiac function was quantified by echocardiography, and plasma leptin and adiponectin concentrations quantified in LF- and HF-fed postpartum and nulliparous females. mRNA abundance of genes regulating cardiac hypertrophy and remodeling was quantified from left ventricles using the NanoString nCounter Analysis System. Cardiac fibrosis was assessed from picrosirius red staining of left ventricles.. HF-fed postpartum mice had markedly greater weight gain and fat mass expansion with obesity, associated with significantly increased LV mass, cardiac output, and stroke volume compared with HF-fed nulliparous mice. Plasma leptin, but not adiponectin, concentrations were correlated with LV mass in HF-fed females. HF feeding increased LV posterior wall thickness; however, LV chamber diameter was only increased in HF-fed postpartum females. Despite the marked increase in LV mass in HF-fed postpartum mice, mRNA abundance of genes regulating fibrosis and interstitial collagen content was similar between HF-fed nulliparous and postpartum mice. In contrast, only HF-fed postpartum mice exhibited altered expression of genes regulating the extracellular matrix.. These results suggest that the combined effects of pregnancy and obesity augment cardiac hypertrophy and promote remodeling. The rising prevalence of CVD in premenopausal women may be attributed to an increased prevalence of women entering pregnancy with an overweight or obese BMI.

Topics: Adiponectin; Animals; Cardiomegaly; Diet, Fat-Restricted; Diet, High-Fat; Female; Heart Ventricles; Leptin; Mice, Inbred C57BL; Obesity; Pregnancy; Transcriptome

White adipocytes are known to function as endocrine organs by secreting a plethora of bioactive adipokines which can regulate cardiac function including the development of hypertrophy. We determined whether adipose tissue conditioned medium (ATCM) generated from the epididymal regions of normal rats can affect the hypertrophic response of cultured rat ventricular myocytes to endothelin-1 (ET-1) administration. Myocytes were treated with ET-1 (10 nM) for 24 hours in the absence or presence of increasing ATCM concentrations. ATCM supressed the hypertrophic response to ET-1 in a concentration-dependent manner, an effect enhanced by the leptin receptor antagonist and attenuated by an antibody against the adiponectin AdipoR1 receptor. Antihypertrophic effects were also observed with ATCM generated from perirenal-derived adipose tissue. However, this effect was absent in ATCM from adipose tissue harvested from corpulent JCR:LA-cp rats. Detailed analyses of adipokine content in ATCM from normal and corpulent rats revealed no differences in the majority of products assayed, although a significant increase in leptin concentrations concomitant with decreased adiponectin levels was observed, resulting in a 11 fold increase in the leptin to adiponectin ratio in ATCM from JCR:LA-cp. The antihypertrophic effect of ATCM was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), an effect abrogated by the AdipoR1 antibody. Moreover, the antihypertrophic effect of ATCM was mimicked by an AMPK activator. There was no effect of ET-1 on mitogen-activated protein kinase (MAPK) activities 24 hour after its addition either in the presence or absence of ATCM. Our study suggests that adipose tissue from healthy subjects exerts antihypertrophic effects via an adiponectin-dependent pathway which is impaired in obesity, most likely due to adipocyte remodelling resulting in enhanced leptin and reduced adiponectin levels.

Topics: Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Cardiomegaly; Cells, Cultured; Culture Media, Conditioned; Endothelin-1; Leptin; Mitogen-Activated Protein Kinases; Myocytes, Cardiac; Obesity; Rats, Sprague-Dawley

The adipokine leptin and its receptor are expressed in the heart, and leptin has been shown to promote cardiomyocyte hypertrophy in vitro. Obesity is associated with hyperleptinemia and hypothalamic leptin resistance as well as an increased risk to develop cardiac hypertrophy and heart failure. However, the role of cardiac leptin signaling in mediating the cardiomyopathy associated with increased body weight is unclear, in particular, whether it develops subsequently to cardiac leptin resistance or overactivation of hypertrophic signaling pathways via elevated leptin levels.. The cardiac phenotype of high-fat diet (HFD)-induced obese wildtype (WT) mice was examined and compared to age-matched genetically obese leptin receptor (LepR)-deficient (LepRdb/db) or lean WT mice. To study the role of leptin-mediated STAT3 activation during obesity-induced cardiac remodeling, mice in which tyrosine residue 1138 within LepR had been replaced with a serine (LepRS1138) were also analyzed.. Obesity was associated with hyperleptinemia and elevated cardiac leptin expression in both diet-induced and genetically obese mice. Enhanced LepR and STAT3 phosphorylation levels were detected in hearts of obese WT mice, but not in those with LepR mutations. Moreover, exogenous leptin continued to induce cardiac STAT3 activation in diet-induced obese mice. Although echocardiography revealed signs of cardiac hypertrophy in all obese mice, the increase in left ventricular (LV) mass and diameter was significantly more pronounced in LepRS1138 animals. LepRS1138 mice also exhibited an increased activation of signaling proteins downstream of LepR, including Jak2 (1.8-fold), Src kinase (1.7-fold), protein kinase B (1.3-fold) or C (1.6-fold). Histological analysis of hearts revealed that the inability of leptin to activate STAT3 in LepRdb/db and LepRS1138 mice was associated with reduced cardiac angiogenesis as well as increased apoptosis and fibrosis.. Our findings suggest that hearts from obese mice continue to respond to elevated circulating or cardiac leptin, which may mediate cardioprotection via LepR-induced STAT3 activation, whereas signals distinct from LepR-Tyr1138 promote cardiac hypertrophy. On the other hand, the presence of cardiac hypertrophy in obese mice with complete LepR signal disruption indicates that additional pathways also play a role.

Topics: Animals; Cardiomegaly; Echocardiography; Immunohistochemistry; Leptin; Mice; Mice, Transgenic; Mutation; Obesity; Phenotype; Receptors, Leptin; Serine; Signal Transduction; STAT3 Transcription Factor; Tyrosine

Apelin has been recognized as an adipokine that plays an important role in regulating energy metabolism and is credited with antiobesity and antidiabetic properties. This study was designed to examine the effect of exogenous apelin on obesity-associated cardiac dysfunction. Oral glucose tolerance test, echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were assessed in adult C57BL/6J mice fed - low or a - high-fat diet for 24weeks followed by apelin treatment (100nmol/kg, i.p. for 2weeks). High-fat diet resulted in increased left ventricular diastolic and systolic diameters, and wall thickness, compromised fractional shortening, impaired cardiomyocyte mechanics (peak-shortening, maximal velocity of shortening/relengthening, and duration of shortening and relengthening) and compromised intracellular Ca(2+) handling, all of which were reconciled by apelin. Apelin treatment also reversed high fat diet-induced changes in intracellular Ca(2+) regulatory proteins, ER stress, and autophagy. In addition, microRNAs (miR) -133a, miR-208 and miR-1 which were elevated following high-fat feeding were attenuated by apelin treatment. In cultured cardiomyocytes apelin reconciled palmitic acid-induced cardiomyocyte contractile anomalies. Collectively, these data depict a pivotal role of apelin in obesity-associated cardiac contractile dysfunction, suggesting a therapeutic potential of apelin in the management of cardiac dysfunction associated with obesity.

Topics: Adipokines; Animals; Apelin; Autophagy; Body Weight; Cardiomegaly; Cells, Cultured; Diet, High-Fat; Endoplasmic Reticulum Stress; Female; Gene Expression Regulation; Glucose; Intercellular Signaling Peptides and Proteins; Leptin; Mice; MicroRNAs; Mitochondria, Heart; Myocardial Contraction; Myocytes, Cardiac; Palmitic Acid; Triglycerides

Leptin, a product of the obesity gene, has been shown to produce cardiac hypertrophy. Although leptin's mechanism of action is poorly understood activation of the RhoA/ROCK pathway has been proposed as a contributing mechanism. The Ca(2+)-dependent phosphatase calcineurin plays a critical role in the hypertrophic program although it is not known whether leptin can activate this signaling pathway or whether there is a relationship between RhoA activation and calcineurin. Accordingly, we determined the effect of leptin on calcineurin activation and assessed the possible role of RhoA. Experiments were performed using cultured neonatal rat ventricular myocytes exposed to 50 ng/ml leptin for 24h which resulted in a robust hypertrophic response. Moreover, leptin significantly increased intracellular Ca(2+) and Na(+) concentrations which was associated with significantly reduced activity of the 3Na(+)-2K(+)ATPase. The hypertrophic response to leptin were completely abrogated by both C3 exoenzyme (C3), a RhoA inhibitor as well as the reverse mode 3Na(+)-1Ca(2+) exchange inhibitor KB-R7943 ((2-[2-[4-(4-nitrobenzyloxy)phenyl] ethyl]isothiourea methanesulfonate), however only the effect of the latter was associated with attenuation of intracellular Ca(2+) concentrations whereas Ca(2+) concentrations were unaffected by C3. Similarly, C3 and KB-R7943 significantly attenuated early leptin-induced increase in calcineurin activity as well as the increase in nuclear translocation of the transcriptional factor nuclear factor of activated T cells. The hypertrophic response to leptin was also associated with increased p38 and ERK1/2 MAPK phosphorylation and increased p38, but not ERK1/2, translocation into nuclei. Both p38 responses as well as hypertrophy were abrogated by KB-R7943 as well as the calcineurin inhibitor FK-506 although ERK1/2 phosphorylation was unaffected. Our study therefore demonstrates a critical role for the calcineurin pathway in mediating leptin-induced hypertrophy. Moreover, we report a novel RhoA-dependent leptin-induced calcineurin activation which acts independently of changes in intracellular Ca(2+) concentrations.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Cardiomegaly; Cell Nucleus; Cells, Cultured; Leptin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocytes, Cardiac; NFATC Transcription Factors; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; rhoA GTP-Binding Protein; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Tacrolimus; Thiourea; Translocation, Genetic

Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNFα), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNFα on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35 min of global ischaemia) followed by 45 min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNFα associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC.

Topics: Animals; Cardiomegaly; Diabetes Mellitus, Type 1; Dietary Carbohydrates; Disease Susceptibility; Heart; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Ischemic Postconditioning; Leptin; Mice; Mice, Knockout; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Obesity; Organ Size; Severity of Illness Index; Streptozocin; Tumor Necrosis Factor-alpha

The traditionally accepted mechanism for ventricular adaptation to obesity suggests that cavity dilatation in response to increased blood volume and elevated filling pressure results in ventricular hypertrophy as a compensatory mechanism. Our hypothesis was that, instead, initiation of ventricular hypertrophy in obesity may be explained by changes in hormonal milieu and not by cavity dilatation.. 88 female subjects without identifiable cardiovascular risk factors, covering a wide range of body mass indices (BMI), from normal (21.2 ± 1.6 kg/m(2)) to severely obese (45.0 ± 4.6 kg/m(2)), underwent cardiovascular MRI to determine left ventricular (LV) and right ventricular (RV) mass and volumes.. BMI correlated positively with LV and RV mass and end-diastolic volumes (EDV). However overweight is associated with a significant LV and RV hypertrophy (LV: 78 ± 11 g vs 103 ± 16 g, p<0.01; RV: 26 ± 7 g vs 40 ± 11 g, p<0.01) was observed in the absence of differences in LV and RV volumes (LV: EDV 119 ± 15 vs 121 ± 21 ml, p>0.99, RV: 131 ± 17 vs 130 ± 24 ml; p>0.99). Furthermore, significant increases of serum leptin occurred at this pre-obese stage (15.6 ± 19 vs 36.5 ± 22 ng/ml; p=0.013).. In a cohort of healthy female subjects with a wide range of BMIs, ventricular hypertrophy occurs without associated cavity dilatation in overweight individuals, while in manifest obesity, both cavity dilatation and ventricular hypertrophy occur. Elevated leptin levels may have a role in this effect on ventricular mass.

Topics: Adult; Body Mass Index; Cardiomegaly; Cohort Studies; Female; Humans; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Insulin; Insulin Resistance; Leptin; Magnetic Resonance Imaging; Middle Aged; Obesity; Ventricular Function, Left; Ventricular Function, Right

Leptin is a 16-kDa peptide primarily derived from white adipocytes and is typically elevated in plasma of obese individuals. Although leptin plays a critical role in appetite regulation, leptin receptors have been identified in numerous tissues including the heart and have been shown to directly mediate cardiac hypertrophy through RhoA/ROCK (Ras homolog gene family, member A/Rho-associated, coiled-coil containing protein kinase)-dependent p38 mitogen-activated protein kinase (MAPK) activation; however, the basis for RhoA stimulation is unknown. Rho guanine nucleotide exchange factors (GEFs) catalyze the exchange of GDP for GTP resulting in Rho activation and may be the potential upstream factors mediating leptin-induced RhoA activation and therefore a potential target for inhibition. We investigated the effects of North American ginseng (Panax quinquefolius), reported to reduce cardiac hypertrophy, on RhoA/ROCK and MAPK activation in ventricular cardiomyocytes exposed to leptin (50 ng/ml) and the possible role of p115RhoGEF and p63RhoGEF in these responses. Leptin produced a robust hypertrophic response that was associated with RhoA/ROCK activation resulting in a significant increase in cofilin-2 phosphorylation and actin polymerization, the latter evidenced by a reduction in the G/F actin ratio. These effects were prevented by ginseng (10 μg/ml). The stimulation of RhoA/ROCK by leptin was associated with significantly increased p115RhoGEF gene and protein expression and exchange activity, all of which were completely prevented by ginseng. The ability of ginseng to prevent leptin-induced activation of RhoA/ROCK was further associated with diminished p38 MAPK activation and nuclear translocation. These results demonstrate a potent inhibitory effect of ginseng against leptin-induced cardiac hypertrophy, an effect associated with prevention of p115RhoGEF-RhoA/ROCK-dependent p38 MAPK activation.

Topics: Actins; Animals; Cardiomegaly; Cardiotonic Agents; Cofilin 2; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Guanine Nucleotide Exchange Factors; Heart Ventricles; Humans; Leptin; Mitogen-Activated Protein Kinases; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Panax; Phosphorylation; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Rho Guanine Nucleotide Exchange Factors; rho-Associated Kinases; rhoA GTP-Binding Protein

1. Our previous study has shown that leptin induces cardiomyocyte hypertrophy; however, the mechanisms are poorly understood. Recent studies have shown that peroxisome proliferator-activated receptor α (PPARα) activation might be responsible for pathological remodeling and severe cardiomyopathy. Leptin, as an endogenous activator of PPARα, regulates energy metabolism through activating PPARα in many cells. Therefore, we hypothesized that leptin induces cardiomyocyte hypertrophy through activating the cardiac PPARα pathway. 2. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of PPARα on hypertrophy. The selective PPARα antagonist GW6471 concentration-dependently decreased atrial natriuretic factor mRNA expression by 23%, 36%, 44% and 59%, and significantly decreased total RNA levels, protein synthesis and cell surface areas, all of which were elevated by 72h of leptin treatment. The augmentation of reactive oxygen species levels in leptin treated cardiomyocytes was reversed by 0.1-10μmol/L GW6471 (40%, 52% and 58%). After 24h of treatment, leptin concentration-dependently enhanced mRNA expression by 7%, 93%, 100% and 256%, and protein expression by 31.2%, 64.2%, 143% and 199%, and the activity of PPARα. Meanwhile, cardiomycytes receiving 72h of treatment with the PPARα agonist, fenofibrate, concentration-dependently increased total RNA levels, atrial natriuretic factor mRNA expression, protein synthesis and cell surface area. Treatment of fenofibrate for 4 h also elevated oxygen species levels in a concentration-dependent manner. 3. In conclusion, these findings show that leptin induces hypertrophy through the activation of the PPARα pathway in cultured neonatal rat cardiomyocytes.

Topics: Animals; Animals, Newborn; Blotting, Western; Cardiomegaly; Cell Culture Techniques; Cell Enlargement; Cells, Cultured; Dose-Response Relationship, Drug; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Leptin; Myocytes, Cardiac; Obesity; Oxazoles; PPAR alpha; Protein Binding; Rats; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Tyrosine

Cardiac injury induced by isoprenaline produces stress. This stress can be mediated by the activated endothelin and leptin pathway; thus, the endothelin receptor antagonist CPU0213 may reverse these changes. CPU0213 is metabolized mainly by cytochrome P450 (CYP)3A, thus, erythromycin, an inhibitor of CYP3A, could affect its effects by raising its plasma levels.. Forty rats were divided into five groups. Group 1 rats were normal. Group 2 rats were administered isoprenaline (1 mg/kg, s.c.) for 10 days. Groups 3, 4 and 5 were administered isoprenaline, but group 3 was given erythromycin (100 mg/kg, p.o.) alone on days six to ten, group 4 was given CPU0213 20 mg/kg (s.c.) on days six to ten, whilst group 5 received erythromycin plus CPU0213 on days six to ten. Measurements were conducted to observe changes in the haemodynamics, cardiac weight index, serum lactate dehydrogenase and creatine kinase levels, and expression of endothelin receptor A (ETA), leptin and its OBRb receptor.. In isoprenaline-treated rats, cardiac hypertrophy and dysfunction were found. This was associated with upregulated myocardial leptin protein and OBRb receptor mRNA. Immunohistochemical assay of ETA was upregulated, accompanied with downregulation of FKBP12.6 (calstabin 2) in isoprenaline-treated rats. These effects were significantly reversed by CPU0213. HPLC assay presented an increased plasma level of CPU0213 by erythromycin, but no change in its effects.. CPU0213 improved isoprenaline-induced cardiomyopathy by modulating ETA, leptin and FKBP12.6. However, erythromycin increased plasma levels but did not change its effects.

Topics: Animals; Cardiomegaly; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Down-Regulation; Endothelin Receptor Antagonists; Erythromycin; Heart Failure; Hemodynamics; Isoproterenol; Leptin; Male; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; Tacrolimus Binding Proteins; Up-Regulation

The interaction of salt sensitivity and obesity in development of cardiac hypertrophy is incompletely understood. The SHHF/Mcc-fa(cp) (SHHF) rat model was used to examine the effect of high salt on cardiac hypertrophy and expression of endothelin (ET) and nitric oxide synthase (NOS) isoforms. Homozygous lean (+/+) and obese (fa(cp)/fa(cp)) SHHF were fed a low-salt diet (0.3% NaCl) for seven days followed by a high-salt diet (8.0% NaCl) for seven days. To assess the role of ET in mediating cardiac hypertrophy and gene expression with high salt, additional groups were treated with an ET(A)/ET(B) receptor antagonist (bosentan) while on high salt. Obese SHHF showed an increase in systolic blood pressure and cardiac hypertrophy in response to the high-salt diet. High salt resulted in decreased expression of preproET as well as all three NOS isoforms in the Obese, while cytokine induced NOS (iNOS) and neuronal NOS (nNOS) increased in Leans. Though the salt-sensitive component of the hypertension observed in the Obese was prevented by bosentan, cardiac hypertrophy still occurred and expression of all NOS isoforms remained lower in Obese compared to Lean. Endothelial NOS (eNOS) expression increased in the Lean with bosentan. These studies suggest that cardiac hypertrophy is independent of the level of hypertension and may be mediated by altered production of NOS isoforms in salt-sensitive, obese SHHF.

Topics: Animals; Base Sequence; Blood Pressure; Bosentan; Cardiomegaly; DNA Primers; Endothelin Receptor Antagonists; Endothelins; Gene Expression; Heart Failure; Leptin; Male; Nitric Oxide Synthase; Obesity; Rats; RNA, Messenger; Sodium Chloride, Dietary; Sulfonamides

Topics: Animals; Cardiomegaly; Caveolae; Humans; Leptin; MAP Kinase Signaling System; Membrane Microdomains; p38 Mitogen-Activated Protein Kinases; rhoA GTP-Binding Protein; STAT3 Transcription Factor

Leptin is elevated under conditions of both obesity and heart failure (HF), and activation of leptin receptor (ObR) signalling is known to increase in vivo cardiac contractility and to have anti-hypertrophic effects on the left ventricle (LV). However, it is unknown whether ObR signalling is altered in cardiomyocytes after myocardial infarction (MI) leading to HF, or if a deficiency in ObR signalling leads to worse HF.. In separate experimental protocols, C57BL/6J and leptin-deficient (ob/ob) mice underwent open-chest surgery to induce permanent left coronary artery ligation (CAL) or had a sham operation. Subgroups of ob/ob mice examined were lean (food-restricted), obese (food-ad libitum), and leptin repleted. Four weeks post-surgery, cardiac structure and function was examined by echocardiography, and the activation of cardiac leptin signalling was characterized through quantitative PCR, western blotting, and DNA-binding activities. CAL produced echocardiographic evidence of HF in C57BL/6J mice, elevated circulating leptin, increased cardiomyocyte leptin and ObR expression, and activated myocardial signal transducer and activator of transcription-3 (STAT3). In leptin-deficient ob/ob mice, whether lean or obese, CAL caused increased hypertrophy and dilation, decreased contractility of the LV, and worsened survival relative to wildtype or leptin-repleted mice after CAL. In ob/ob mice, activation of cardiac STAT3 signalling after CAL is enhanced in the presence of leptin and parallels the induction of the STAT3-responsive genes, tissue-inhibitor of metalloproteinase-1 and heat shock protein-70.. These data demonstrate that HF increases ObR signalling in cardiomyocytes and that activation of ObR signalling improves functional outcomes in chronic ischaemic injury leading to HF.

Topics: Animals; Cardiomegaly; Heart; Heart Failure; Leptin; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Ventricular Function, Left

Leptin-induced cardiomyocyte hypertrophy is dependent on both RhoA and p38 mitogen-activated protein kinase (p38 MAPK) activation. The present study investigated the role of lipid raft/caveolae in these responses and assessed the nature of p38 MAPK activation in mediating leptin-induced hypertrophy.. Studies were carried out using cultured neonatal rat ventricular myocytes. Pharmacological, molecular, microscopy, and confocal imaging techniques were used to assess the role of caveolae in leptin-induced hypertrophy and to study the underlying cellular mechanisms. Leptin (3.1 nmol/L) treatment for 24 h significantly increased caveolae number two-fold and increased expression of caveolin-3 to 278 +/- 14% of control values. These effects were associated with increased cell surface area by 29 +/- 5% and leucine incorporation by 40 +/- 6%. The hypertrophic effect of leptin was associated with significant activation of RhoA (422 +/- 26%) and a decrease in the G-actin-to-F-actin ratio from 3.1 +/- 0.2 to 0.9 +/- 0.1. Caveolae disruption with methyl-beta-cyclodextrin (MbetaCD) potently attenuated leptin-induced cell hypertrophy and the associated signalling. RhoA was detected in caveolae fraction of a sucrose gradient after treatment with leptin for 5 min, indicating subcellular translocation of RhoA: this effect was inhibited by MbetaCD, the RhoA inhibitor C3 exoenzyme, and by disruption of actin filaments with latrunculin B. Furthermore, leptin-induced hypertrophy was associated with p38 MAPK but not with extracellular signal-regulated kinase (ERK1/2) translocation to nuclei, which was inhibited by MbetaCD, C3 exoenzyme, and the Rho kinase inhibitor Y-27632.. Our results indicate that p38 import into nuclei represents a key mechanism for leptin-induced hypertrophy acting through lipid raft/caveolae and a RhoA-dependent pathway.

Topics: Actins; Active Transport, Cell Nucleus; Animals; Cardiomegaly; Caveolae; Cell Nucleus; Cells, Cultured; Cholesterol; Extracellular Signal-Regulated MAP Kinases; Leptin; Membrane Microdomains; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; rho GTP-Binding Proteins; rhoA GTP-Binding Protein

Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, db/db, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110alpha) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110alpha catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.

Topics: Animals; Apoptosis; Cardiomegaly; Caspase 3; Catalysis; Class I Phosphatidylinositol 3-Kinases; Heart Failure; Leptin; Mice; Mice, Obese; Muscle Cells; Myocardium; Phosphatidylinositol 3-Kinases

A number of investigators have observed insufficient 25-hydroxyvitamin D status in patients with congestive heart failure, suggesting a role for vitamin D insufficiency in the pathogenesis of this disorder. We have observed cardiac hypertrophy and collagen accumulation in rats deficient in vitamin D and in the hearts of vitamin D-receptor knockout mice. Our studies indicate that absence of vitamin D-mediated signal transduction and genomic activation results in cardiomyocytes overstimulation including increased contractility. These events ultimately lead to cardiomyocyte hypertrophy. In this report, we used spontaneously hypertensive heart failure rats cp/+ (hemyzygous for the corpulent gene, a mutant isoform of the leptin receptor) fed a normal and a high-salt diet to assess the potential for activated vitamin D (1,25 dihydroxyvitamin D3) to prevent cardiac hypertrophy and increases in cardiac output. After 13 weeks, as compared with untreated rats, we observed that 1,25 dihydroxyvitamin D3 treatment in rats fed a high-salt diet resulted in lower heart weight, myocardial collagen levels, left ventricular diameter, and cardiac output despite higher serum leptin levels. These studies suggest that 1,25(OH)2D3 treatment may prevent the development of cardiac hypertrophy, an important contributing factor in the progression of congestive heart failure.

Topics: Animals; Brain; Calcitriol; Calcium; Cardiac Output; Cardiomegaly; Collagen; Echocardiography; Female; Heart Failure; Hypertrophy, Left Ventricular; Leptin; Magnesium; Male; Mutation; Myocardium; Organ Size; Phosphates; Rats; Rats, Inbred SHR; Receptors, Leptin; Tibia; Vitamins

Disruption of leptin signaling is associated with obesity, heart failure, and cardiac hypertrophy, but the role of leptin in cardiac myocyte apoptosis is unknown. We tested the hypothesis that apoptosis increases in leptin-deficient ob/ob and leptin-resistant db/db mice and is associated with aging and left ventricular hypertrophy, increased DNA damage, and decreased survival. We studied young (2- to 3-month-old) and old (12- to 14-month-old) ob/ob and db/db mice and wild-type (WT) controls (n=2 to 4 per group). As expected, ventricular wall thickness and heart weights were similar among young ob/ob, db/db, and WT mice, but higher in old ob/ob and db/db versus old WT. Young ob/ob and db/db showed markedly elevated apoptosis by TUNEL staining and caspase 3 levels compared with WT. Differences in apoptosis were further accentuated with age. Leptin treatment significantly reduced apoptosis in ob/ob mice both in intact hearts and isolated myocytes. Tissue triglycerides were increased in ob/ob hearts, returning to WT levels after leptin repletion. Furthermore, the DNA damage marker, 8oxoG (8-oxo-7,8-dihydroguanidine), was increased, whereas the DNA repair marker, MYH glycosylase, was decreased in old ob/ob and db/db compared with old WT mice. Both ob/ob and db/db mice had decreased survival compared with WT mice. We conclude that leptin-deficient and leptin-resistant mice demonstrate increased apoptosis, DNA damage, and mortality compared with WT mice, suggesting that normal leptin signaling is necessary to prevent excess age-associated DNA damage and premature mortality. These data offer novel insights into potential mechanisms of myocardial dysfunction and early mortality in obesity.

Topics: Animals; Apoptosis; Cardiomegaly; DNA Damage; DNA Repair; In Situ Nick-End Labeling; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Myocytes, Cardiac; Obesity; Oxidative Stress; Signal Transduction; Triglycerides

Leptin is a 16 kDa product of the obesity gene secreted primarily by adipocytes. We recently identified cardiomyocytes as a target for the direct hypertrophic effects of leptin and suggested that leptin may be a biological link between obesity and cardiovascular pathologies. Activation of the renin-angiotensin and endothelin systems is associated with development of cardiovascular diseases and plasma renin levels are elevated in obese individuals. We therefore determined possible interaction between these factors in mediating hypertrophy in cultured neonatal rat ventricular myocytes. Treatment for 24 h with leptin (3.1 nM), angiotensin II (100 nM) or endothelin-1 (ET-1, 10 nM) significantly increased cell area by 37%, 36% and 35%, respectively and significantly increased gene expression of myosin light chain-2 and alpha-skeletal actin as well as leucine incorporation. The hypertrophic effects of all three agents were prevented by leptin and a leptin triple mutant receptor antagonist whereas the AT(1) receptor blocker (Sar1-lle(8))-Ang II or the ET(A) receptor blocker BQ123 was ineffective against leptin-induced hypertrophy. Both angiotensin II and ET-1 significantly increased leptin levels in the culture medium by fivefold. Moreover, both angiotensin II and ET-1 increased the gene expression of the short form (OBRa) by 180% and long form (OBRb) of leptin receptors by 200%, and this increase was abolished by both leptin receptor and leptin antibodies and leptin triple mutant. Although both angiotensin II and ET-1 increased phosphorylation of MAPK (p38, ERK1/2 and JNK) and NF-kappaB, the ability of leptin blockade to attenuate the hypertrophic responses was generally dissociated from these effects suggesting an alternate, yet to be identified cellular pathway mediating this role of leptin. Our studies therefore suggest a novel autocrine function for leptin in mediating the hypertrophic effects of both angiotensin II and ET-1 in cardiac myocytes.

Topics: Adipocytes; Angiotensin II; Animals; Animals, Newborn; Autocrine Communication; Cardiomegaly; Cells, Cultured; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Leptin; MAP Kinase Signaling System; Myocytes, Cardiac; Obesity; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents

Impaired leptin signalling in obesity is increasingly implicated in cardiovascular pathophysiology. To explore mechanisms for leptin activity in the heart, we hypothesized that physiological leptin signalling participates in maintaining cardiac beta-adrenergic regulation of excitation-contraction coupling. We studied 10-week-old (before development of cardiac hypertrophy) leptin-deficient (ob/ob, n=12) and C57Bl/6 (wild-type (WT), n=15) mice at baseline and after recombinant leptin infusion (0.3 mg kg-1 day-1 for 28 days, n=6 in each group). Ob/ob-isolated myocytes had attenuated sarcomere shortening and calcium transients ([Ca2+]i) versus WT (P<0.01 for both) following stimulation of the beta-receptor (with isoproterenol (isoprenaline)) or at the post-receptor level (with forskolin and dibutryl-cAMP). In addition, sarcoplasmic reticulum (SR) Ca2+ stores were depressed. Leptin replenishment in ob/ob mice restored each of these abnormalities towards normal without affecting gross (wall thickness) or microscopic (cell size) measures of cardiac architecture. Immunoblots revealed alterations of several proteins involved in excitation-contraction coupling in the ob/ob mice, including decreased abundance of Gsalpha-52 kDa, as well as alterations in the expression of Ca2+ cycling proteins (increased SR Ca2+-ATPase, and depressed phosphorylated phospholamban). In addition, protein kinase A (PKA) activity in ob/ob mice was depressed at baseline and correctable towards the activity found in WT with leptin repletion, a finding that could account for impaired beta-adrenergic responsiveness. Taken together, these data reveal a novel link between the leptin signalling pathway and normal cardiac function and suggest a mechanism by which leptin deficiency or resistance may lead to cardiac depression.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Age Factors; Animals; Blotting, Western; Calcium; Cardiomegaly; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Isoproterenol; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Myocardial Contraction; Obesity; Phenotype; Receptors, Adrenergic, beta; Receptors, Leptin; Sarcoplasmic Reticulum; Signal Transduction

Obesity is a major risk factor for the development of cardiovascular disease. Emerging evidence indicates that leptin, a protein encoded by the obesity gene, is linked with cardiac hypertrophy in obese humans and directly induces cardiomyocyte hypertrophy in vitro. However, the mechanisms by which leptin induces cardiomyocyte hypertrophy are poorly understood.. This study investigated how leptin contributes to cardiomyocyte hypertrophy. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of leptin on hypertrophy. Both endothelin-1 (ET-1) and reactive oxygen species (ROS) levels were elevated in a concentration-dependent manner in cardiomyocytes treated with leptin for 4 hours compared with those cells without leptin treatment. ET-1 stimulated ROS production in a concentration-dependent manner in cardiomyocytes. The augmentation of ROS levels in cardiomyocytes treated with both leptin and ET-1 was reversed by a selective ET(A) receptor antagonist, ABT-627, and catalase, a hydrogen peroxide-decomposing enzyme. After treatment for 72 hours, leptin or ET-1 concentration-dependently increased total RNA levels, cell surface areas, and protein synthesis in cardiomyocytes, all of which were significantly inhibited by ABT-627 or catalase treatment.. These findings indicate that leptin elevates ET-1 and ROS levels, resulting in hypertrophy of cultured neonatal rat cardiac myocytes. The ET-1-ET(A)-ROS pathway may be involved in cardiomyocyte hypertrophy induced by leptin. ET(A) receptor antagonists and antioxidant therapy may provide an effective means of ameliorating cardiac dysfunction in obese humans.

Topics: Animals; Animals, Newborn; Antioxidants; Atrasentan; Atrial Natriuretic Factor; Cardiomegaly; Catalase; Cell Size; Cells, Cultured; Endothelin A Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Leptin; Myocytes, Cardiac; Obesity; Oxidative Stress; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Diseases due to mutations in the lamin A/C gene (LMNA) are highly heterogeneous, including neuromuscular and cardiac dystrophies, lipodystrophies, and premature ageing syndromes. In this study we characterized the neuromuscular and cardiac phenotypes of patients bearing the heterozygous LMNA R482W mutation, which is the most frequent genotype associated with the familial partial lipodystrophy of the Dunnigan type (FPLD). Fourteen patients from two unrelated families, including 10 affected subjects, were studied. The two probands had been referred for lipoatrophy and/or diabetes. Lipodystrophy, exclusively observed in LMNA-mutated patients, was of variable severity and limited to postpubertal subjects. Lipodystrophy and metabolic disturbances were more severe in women, even if an enlarged neck was a constant finding. The severity of hypertriglyceridemia and hirsutism in females was related to that of insulin resistance. Clinical muscular alterations were only present in LMNA-mutated patients. Clinical and histological examination showed an invalidating, progressive limb-girdle muscular dystrophy in a 42-yr-old woman that had been present since childhood, associated with a typical postpubertal FPLD phenotype. Six of eight adults presented the association of calf hypertrophy, perihumeral muscular atrophy, and a rolling gait due to proximal lower limb weakness. Muscular histology was compatible with muscular dystrophy in one of them and/or showed a nonspecific excess of lipid droplets (in three cases). Immunostaining of lamin A/C was normal in the six muscular biopsies. Surprisingly, calpain 3 expression was undetectable in the patient with the severe limb-girdle muscular dystrophy, although the gene did not reveal any molecular alterations. At the cardiac level, cardiac septal hypertrophy and atherosclerosis were frequent in FPLD patients. In addition, a 24-yr-old FPLD patient had a symptomatic second degree atrioventricular block. In conclusion, we showed that most lipodystrophic patients affected by the FPLD-linked LMNA R482W mutation show muscular and cardiac abnormalities. The occurrence and severity of the myopathic and lipoatrophic phenotypes varied and were not related. The muscular phenotype was evocative of limb girdle muscular dystrophy. Cardiac hypertrophy and advanced atherosclerosis were frequent. FPLD patients should receive careful neuromuscular and cardiac examination whatever the underlying LMNA mutation.

Topics: Adolescent; Adult; Arteriosclerosis; Calpain; Cardiomegaly; Child; Diabetes Mellitus, Lipoatrophic; Female; Humans; Lamin Type A; Leptin; Male; Middle Aged; Muscles; Muscular Dystrophies, Limb-Girdle; Mutation; Triglycerides

Whether left ventricular hypertrophy (LVH) in obesity results from increased hemodynamic load or altered neurohormonal signaling remains controversial. Dysregulation of leptin, a neurohormone essential to energy homeostasis, is implicated in the pathogenesis of obesity. Because leptin has cardiovascular bioactivity, we hypothesized that disruption of leptin signaling mediates the development of obesity-associated LVH.. We measured left ventricular (LV) wall thickness and LV mass with echocardiography in mice lacking leptin (ob/ob, n=15) or functional receptor (db/db, n=10) and controls at 2, 4, and 6 months of age. None of the mice had LVH at 2 months. Progressive obesity developed in ob/ob and db/db mice. At 6 months, LVH occurred in ob/ob and db/db compared with controls. We observed corresponding myocyte hypertrophy by light microscopy. To separate the direct contribution of leptin deficiency from mechanical effects of obesity, we induced weight loss in 6- to 8-month-old ob/ob mice either by leptin infusion or caloric restriction. Mice in both groups lost similar weight compared with placebo-treated controls. Leptin infusion completely reversed the increase in wall thickness with partial resolution of myocyte hypertrophy, whereas calorie-restricted mice had no decrease in wall thickness and a lesser change in myocyte size.. Together these data show that the effect of leptin on LV remodeling is not attributable to weight loss alone, indicating that leptin has antihypertrophic effects on the heart, either directly or through a leptin-regulated neurohumoral pathway. Disruption of leptin signaling may represent a novel mechanism in LVH and related cardiovascular disorders.

Topics: Animals; Body Weight; Cardiomegaly; Disease Models, Animal; Disease Progression; Heart Ventricles; Hemodynamics; Homozygote; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myocardium; Myocytes, Cardiac; Obesity; Organ Size; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Ventricular Remodeling