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Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects.

ABSTRACT: BACKGROUND AND PURPOSE: Protection against ischaemia-reperfusion (I/R) injury involves PI3K-Akt and p44/42 MAPK activation. Leptin which regulates appetite and energy balance also promotes myocyte proliferation via PI3K-Akt and p44/42 MAPK activation. We, therefore, hypothesized that leptin may also exhibit cardioprotective activity. EXPERIMENTAL APPROACH: The influence of leptin on I/R injury was examined in perfused hearts from C57Bl/6 J mice that underwent 35 min global ischaemia and 35 min reperfusion, infarct size being assessed by triphenyltetrazolium chloride staining. The concomitant activation of cell-signalling pathways was investigated by Western blotting. The effect of leptin on mitochondrial permeability transition pore (MPTP) opening was studied in rat cardiomyocytes. KEY RESULTS: Leptin (10 nM) administered during reperfusion reduced infarct size significantly. Protection was blocked by either LY294002 or UO126, inhibitors of Akt and p44/42 MAPK, respectively. Western blotting confirmed that leptin stimulated p44/42 MAPK phosphorylation significantly. Akt phosphorylation was also enhanced but did not achieve statistical significance. Additionally, leptin treatment was associated with a significant increase in p38 phosphorylation. By contrast, leptin caused downregulation of phosphorylated and non-phosphorylated STAT3, and of total AMP-activated kinase. Cardiomyocytes responded to leptin with delayed opening of the MPTP and delayed time until contracture. CONCLUSIONS AND IMPLICATIONS: Our data indicate for the first time that the adipocytokine, leptin, has direct cardioprotective properties which may involve the PI3-Akt and p44/42 MAPK pathways.

SUBMITTER: Smith CC

PROVIDER: S-EPMC1629412 | biostudies-other | 2006 Sep

REPOSITORIES: biostudies-other

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Project description:BackgroundAdipose tissue is producing adipokines that play different roles in the pathophysiology of cardiovascular disease.AimsThe study aimed to assess the role of selected biomarkers in hypertensive patients with overweight and obesity compared with those with normal body-mass index (BMI).MethodsA total of 62 patients with BMI < 25 kg/m2 (median age 54 (46-58) yrs., 57% males) and 51 with BMI ≥ 25 kg/m2 (median age 53 (48-59) yrs., 37% males) were enrolled. Biochemical parameters, leptin, adiponectin, and resistin; asymmetric dimethylarginine; interleukin 6; and N-terminal propeptide of type III procollagen, were assessed in plasma. The evaluation of hemodynamic parameters was performed using SphygmoCor 9.0 tonometer. Echocardiography was performed using AlokaAlpha 10 Premier device.ResultsOverweight and obese patients had significantly higher concentration of leptin (34 vs 18 ng/ml; p = 0.03), ADMA (0.43 vs 0.38 μmol/l, p = 0.04), and lower concentration of adiponectin (5.3 vs 7 μg/ml, p = 0.01). The only significant difference in tonometry analysis was higher aortic pulse pressure (mmHg) in patients with BMI ≥ 25 kg/m2 group (34 vs 30; p = 0.03). These patients had also significantly lower peak systolic velocity and early diastolic velocity in tissue Doppler imaging of the right ventricle free wall at the level of the tricuspid annulus compared with controls (p = 0.02 and p = 0.001, respectively). The level of leptin is correlated negatively with the left ventricular mass index (LVMI) (R Spearman = - 0.5; p = 0.002) and PWV (R = - 0.4; p = 0.01) and ADMA with total and LDL cholesterol (R = - 0.42; p = 0.008), and adiponectin is correlated positively with HDL cholesterol (R = 0.67; p = 0.0001).ConclusionsLeptin concentrations were inversely proportional to LVMI and PWV in patients with BMI < 25 kg/m2.Trial registrationClinicaltrials.gov study ID: NCT04175080.

Project description:Leptin is thought to exert its actions on energy homeostasis through the long form of the leptin receptor (OB-Rb), which is present in the hypothalamus and in certain peripheral organs, including adipose tissue. In this study, we examined whether leptin has direct effects on the function of brown and white adipose tissue (BAT and WAT, respectively) at the metabolic and molecular levels. The chronic peripheral intravenous administration of leptin in vivo for 4 d resulted in a 1.6-fold increase in the in vivo glucose utilization index of BAT, whereas no significant change was found after intracerebroventricular administration compared with pair-fed control rats, compatible with a direct effect of leptin on BAT. The effect of leptin on WAT fat pads from lean Zucker Fa/ fa rats was assessed ex vivo, where a 9- and 16-fold increase in the rate of lipolysis was observed after 2 h of exposure to 0.1 and 10 nM leptin, respectively. In contrast, no increase in lipolysis was observed in the fat pads from obese fa/fa rats, which harbor an inactivating mutation in the OB-Rb. At the level of gene expression, leptin treatment for 24 h increased malic enzyme and lipoprotein lipase RNA 1.8+/-0.17 and 1.9+/-0.14-fold, respectively, while aP2 mRNA levels were unaltered in primary cultures of brown adipocytes from lean Fa/fa rats. Importantly, however, no significant effect of leptin was observed on these genes in brown adipocytes from obese fa/fa animals. The presence of OB-Rb receptors in adipose tissue was substantiated by the detection of its transcripts by RT-PCR, and leptin treatment in vivo and in vitro activated the specific STATs implicated in the signaling pathway of the OB-Rb. Taken together, our data strongly suggest that leptin has direct effects on BAT and WAT, resulting in the activation of the Jak/STAT pathway and the increased expression of certain target genes, which may partially account for the observed increase in glucose utilization and lipolysis in leptin-treated adipose tissue.

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Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects.

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