Cardiovascular effects of leptin and orexins

Department of Anesthesiology, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.53). 04/2003; 284(3):R639-51. DOI: 10.1152/ajpregu.00359.2002
Source: PubMed

ABSTRACT Leptin, the product of the ob gene, is a satiety factor secreted mainly in adipose tissue and is part of a signaling mechanism regulating the content of body fat. It acts on leptin receptors, most of which are located in the hypothalamus, a region of the brain known to control body homeostasis. The fastest and strongest hypothalamic response to leptin in ob/ob mice occurs in the paraventricular nucleus, which is involved in neuroendocrine and autonomic functions. On the other hand, orexins (orexin-A and -B) or hypocretins (hypocretin-1 and -2) were recently discovered in the hypothalamus, in which a number of neuropeptides are known to stimulate or suppress food intake. These substances are considered important for the regulation of appetite and energy homeostasis. Orexins were initially thought to function in the hypothalamic regulation of feeding behavior, but orexin-containing fibers and their receptors are also distributed in parts of the brain closely associated with the regulation of cardiovascular and autonomic functions. Functional studies have shown that these peptides are involved in cardiovascular and sympathetic regulation. The objective of this article is to summarize evidence on the effects of leptin and orexins on cardiovascular function in vivo and in vitro and to discuss the pathophysiological relevance of these peptides and possible interactions.

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    ABSTRACT: Background and PurposeOrexins have been demonstrated to play important roles in many physiological processes. However, how orexin A affects hypoglossal motoneuron (HMN) and genioglossus (GG) muscle activity is unknown.Experimental ApproachHere, we recorded GG muscle electromyograms (GG-EMG) in anesthetized adult rats after orexin A or orexin receptor antagonists were applied to the hypoglossal nucleus, and in adult rats which orexin neurons were lesioned with the neurotoxin orexin-saporin (orexin-SAP). HMN membrane potential and firing were recorded from neonatal rat brain slices using whole-cell patch clamp after an infusion of orexin A or orexin receptor antagonists.Key ResultsUnilateral microinjection of orexin A (50, 100, or 200 μM) into the hypoglossal nucleus significantly enhanced ipsilateral GG activity in adult rats. Orexin A (4, 20, 100, or 500 nM) depolarized the resting membrane potential and increased the firing rate of HMNs in a dose-dependent manner in the medullary slices of neonatal rats. Either SB 334867, a specific OX1 receptor antagonist or TCS OX2 29, a specific OX2 receptor antagonist not only blocked the depolarized membrane potential and the increased firing rate of HMNs by orexin A in the neonatal model, but also attenuated GG-EMG in the adult model. A significant decrease in GG-EMG was observed in adult orexin neuron-lesioned rats compared with sham animals.Conclusion and ImplicationsOrexin A, upon the activation of OX1 and OX2 receptors within the hypoglossal motor pool, promotes GG activity, indicating that orexin A is involved in controlling respiratory motor activity.
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    ABSTRACT: 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. 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. 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. 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.
    British Journal of Pharmacology 10/2006; 149(1):5-13. DOI:10.1038/sj.bjp.0706834 · 4.99 Impact Factor
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    ABSTRACT: The obese gene product, leptin, plays a central role in food intake and energy metabolism. The physiological roles of leptin in human bodily function have been broadened over the past decade since leptin was first discovered in 1994. Evidence has suggested that leptin plays a specific role in the intricate cascade of cardiovascular events, in addition to its well-established metabolic effects. Leptin, a hormone linking adiposity and central nervous circuits to reduce appetite and enhance energy expenditure, has been shown to increase overall sympathetic nerve activity, facilitate glucose utilization and improve insulin sensitivity. In addition, leptin is capable of regulating cardiac and vascular contractility through a local nitric oxide-dependent mechanism. However, elevated plasma leptin levels or hyperleptinemia, have been demonstrated to correlate with hyperphagia, insulin resistance and other markers of the metabolic syndrome including obesity, hyperlipidemia and hypertension, independent of total adiposity. Elevated plasma leptin levels may be an independent risk factor for the development of cardiovascular disease. Although mechanisms leading to hyperleptinemia have not been well described, factors such as increased food intake and insulin resistance have been shown to rapidly enhance plasma leptin levels and subsequently tissue leptin resistance. These findings have prompted the speculation that leptin in the physiological range may serve as a physiological regulator of cardiovascular function whereas elevated plasma leptin levels may act as a pathophysiological trigger and/or marker for cardiovascular diseases due to tissue leptin resistance.
    Journal of Endocrinology 05/2004; 181(1):1-10. DOI:10.1677/joe.0.1810001 · 3.59 Impact Factor