Chronic CNS-mediated cardiometabolic actions of leptin: potential role of sex differences

Silva, Alexandre A. da; Pinkerton, Mark; Spradley, Frank T.; Palei, Ana C.; Hall, John E.; Carmo, Jussara M. do

doi:10.1152/ajpregu.00027.2020

Cited by 6 publications

(6 citation statements)

References 34 publications

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“… 21 We also showed that these effects were mediated by the CNS since this dose of leptin infused intracerebroventricular does not increase circulating levels of leptin. 13 In addition, chronic intraperitoneal leptin infusion at the same dose infused intracerebroventricular in the present study (0.62 μg/h) did not alter food intake, body weight, blood pressure, heart rate, blood glucose, or insulin levels in male and female rats. 13 …”

Section: Discussionsupporting

confidence: 45%

“… 13 In addition, chronic intraperitoneal leptin infusion at the same dose infused intracerebroventricular in the present study (0.62 μg/h) did not alter food intake, body weight, blood pressure, heart rate, blood glucose, or insulin levels in male and female rats. 13 …”

Section: Discussionsupporting

confidence: 45%

“…Although intracerebroventricular leptin infusion reduces insulin plasma levels in male and female rats, 13 we have previously shown that insulin‐deficient diabetic rats treated with central leptin also presented cardiovascular improvements, 4 indicating that the cardiometabolic effects of intracerebroventricular leptin administration are independent of insulin. Therefore, we are confident that the beneficial cardiac protective effects of intracerebroventricular leptin infusion after I/R injury are mediated by CNS actions and not by direct peripheral effects of leptin or reductions in plasma insulin levels.…”

Section: Discussionmentioning

confidence: 92%

“…Although some studies suggest that there may be sex differences in leptin's effects on sympathetic activity, our results in the present study and in previous studies suggest that chronic intracerebroventricular leptin infusion appears to alter cardiac function to the same extent in conscious male and female rats. 4 , 13 Additionally, other studies indicate that increases in sympathetic activity and heart rate evoked by intracerebroventricular leptin infusion are similar in male and pro‐estrus female rats. 33 Although levels of estrogen were not measured in the present study, we speculate that intracerebroventricular leptin treatment may potentiate estrogen‐related cardiac protection, contributing to smaller infarcts in leptin‐treated females.…”

Section: Discussionmentioning

confidence: 97%

“…The rate of leptin infusion was based on our previous studies showing this dose is effective in decreasing food intake and improving glucose homeostasis. 6 , 13 …”

Section: Methodsmentioning

confidence: 99%

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Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia–Reperfusion: Roles of Sympathetic Innervation and Sex Differences

Omoto

Carmo

Nelson

et al. 2022

JAHA

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Background Therapeutic strategies for preventing paradoxical reperfusion injury after myocardial ischemia are limited. We tested whether central nervous system actions of leptin induce important protective effects on cardiac function and metabolism after myocardial ischemia/reperfusion (I/R) injury, the role of cardiac sympathetic innervation in mediating these effects, and whether there are major sex differences in the cardioprotective effects of chronic central nervous system leptin infusion. Methods and Results Myocardial I/R was induced by temporary ligation of the left descending coronary artery in male and female Wistar rats instrumented with intracerebroventricular cannula in the lateral ventricle. Vehicle or leptin (0.62 μg/h) infusion was started immediately after reperfusion and continued for 28 days using osmotic minipumps connected to the intracerebroventricular cannula. Cardiac function was assessed by echocardiography, ventricular pressures, and exercise performance. Intracerebroventricular leptin treatment markedly attenuated cardiac dysfunction post‐I/R as evidenced by improved ejection fraction (56.7±1.9 versus 22.6%±1.1%), maximal rate of left ventricle rise (11 680±2122 versus 5022±441 mm Hg) and exercise performance (−4.2±7.9 versus −68.2±3.8 Δ%) compared with vehicle‐treated rats. Intracerebroventricular leptin infusion reduced infarct size in females, but not males, when compared with ad‐lib fed or pair‐fed saline‐treated rats. Intracerebroventricular leptin treatment also increased cardiac NAD + /NADH content (≈10‐fold) and improved mitochondrial function when compared with vehicle treatment. Cervical ganglia denervation did not attenuate the cardiac protective effects of leptin after I/R injury. Conclusions These data indicate that leptin, via its central nervous system actions, markedly improves overall heart function and mitochondrial metabolism after I/R injury regardless of sex, effects that are largely independent of cardiac sympathetic innervation.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 97%

“…The rate of leptin infusion was based on our previous studies showing this dose is effective in decreasing food intake and improving glucose homeostasis. 6 , 13 …”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia–Reperfusion: Roles of Sympathetic Innervation and Sex Differences

Omoto

Carmo

Nelson

et al. 2022

JAHA

Self Cite

View full text Add to dashboard Cite

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Mechanisms of leptin-induced endothelial dysfunction

Mellott¹,

Faulkner

2022

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewEndothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific. This review will summarize recent findings of mechanisms of leptin-induced endothelial impairment in both male and females and in pregnancy.Recent findingsLeptin receptors are found in high concentrations in the central nervous system (CNS), via which leptin promotes appetite suppression and upregulates sympathetic nervous system activation. However, leptin receptors are expressed in many other tissues, including the vascular endothelial cells and smooth muscle cells. Recent studies in mice with vascular endothelial or smooth muscle-specific knockdown demonstrate that endothelial leptin receptor activation plays a protective role against endothelial dysfunction in male animals, but not necessarily in females. Clinical studies indicate that women may be more sensitive to obesity-associated vascular endothelial dysfunction. Emerging preclinical data indicates that leptin and progesterone increase aldosterone production and endothelial mineralocorticoid receptor activation, respectively. Furthermore, decades of clinical studies indicate that leptin levels increase in the hypertensive pregnancy disorder preeclampsia, which is characterized by systemic endothelial dysfunction. Leptin infusion in mice induces the clinical characteristics of preeclampsia, including endothelial dysfunction.SummaryNovel preclinical data indicate that the mechanisms whereby leptin promotes endothelial dysfunction are sex-specific. Leptin-induced endothelial dysfunction may also play a role in hypertensive pregnancy as well.

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Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats

Palei

Martin

Wilson

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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The prevalence of preeclampsia and obesity have increased. While obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in non-pregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On gestational day (GD) 14, Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 mg/kg per min, i.v.) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On GD 19, plasma leptin was elevated in Sham+Leptin and RUPP+Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP+Vehicle vs. Sham+Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared to vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling.

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Chronic CNS-mediated cardiometabolic actions of leptin: potential role of sex differences

Cited by 6 publications

References 34 publications

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia–Reperfusion: Roles of Sympathetic Innervation and Sex Differences

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia–Reperfusion: Roles of Sympathetic Innervation and Sex Differences

Mechanisms of leptin-induced endothelial dysfunction

Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats

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