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: 3.11). 04/2003; 284(3):R639-51. DOI: 10.1152/ajpregu.00359.2002
Source: PubMed


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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    • "As peptide transmitters, orexins, including orexin A and B, have been demonstrated to play an important role in many physiological processes, such as feeding behaviour (Willie et al., 2001), energy homeostasis (Kukkonen et al., 2002), sleep/wake cycles (Saper et al., 2005), motivation (Harris and Aston-Jones, 2006), stress responses (Zhang et al., 2006), regulation of the cardiovascular system (Shirasaka et al., 2003) and breathing (Young et al., 2005). Orexin neurons are restricted to the lateral hypothalamus (LH). "
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    ABSTRACT: Background and purpose: Orexins have been demonstrated to play important roles in many physiological processes. However, it is not known how orexin A affects the activity of the hypoglossal motoneuron (HMN) and genioglossus (GG) muscle. Experimental approach: GG muscle electromyograms (GG-EMG) were recorded in anaesthetized adult rats after orexin A or orexin receptor antagonists were applied to the hypoglossal nucleus, and in adult rats in 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 results: Unilateral micro-injection 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. Both SB 334867, a specific OX1 receptor antagonist and 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 implications: Orexin A activates OX1 and OX2 receptors within the hypoglossal motor pool and promotes GG activity, indicating that orexin A is involved in controlling respiratory motor activity.
    Full-text · Article · May 2014 · British Journal of Pharmacology
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    • "The presence of leptin receptors in the vascular endothelium and not only in the central nervous system is important because it allows to find a link between leptin and altered vascular function in obesity [82]. Leptin is an NO-dependent vasodilator but also increases peripheral vascular resistance and sympathetic nerve activity [83]. The concentration of plasma leptin is correlated with adiposity, and hyperleptinemia is indeed considered an independent cardiovascular disease risk factor [84]. "
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    ABSTRACT: METABOLIC SYNDROME IS A CLUSTER OF METABOLIC AND CARDIOVASCULAR SYMPTOMS: insulin resistance (IR), obesity, dyslipemia. Hypertension and vascular disorders are central to this syndrome. After a brief historical review, we discuss the role of sympathetic tone. Subsequently, we examine the link between endothelial dysfunction and IR. NO is involved in the insulin-elicited capillary vasodilatation. The insulin-signaling pathways causing NO release are different to the classical. There is a vasodilatory pathway with activation of NO synthase through Akt, and a vasoconstrictor pathway that involves the release of endothelin-1 via MAPK. IR is associated with an imbalance between both pathways in favour of the vasoconstrictor one. We also consider the link between hypertension and IR: the insulin hypothesis of hypertension. Next we discuss the importance of perivascular adipose tissue and the role of adipokines that possess vasoactive properties. Finally, animal models used in the study of vascular function of metabolic syndrome are reviewed. In particular, the Zucker fatty rat and the spontaneously hypertensive obese rat (SHROB). This one suffers macro- and microvascular malfunction due to a failure in the NO system and an abnormally high release of vasoconstrictor prostaglandins, all this alleviated with glitazones used for metabolic syndrome therapy.
    Full-text · Article · Mar 2013 · International Journal of Hypertension
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    • "Arterial blood pressure was also significantly higher in this group [68]. It might be speculated that orexin A partially mediates this pressor response by: increasing basal sympathetic activity, causing catecholamine release [95], modulating the vasopressin system [96], and stimulating renal and adrenal orexin receptors [97]. These speculations are further justified by the study of Shiraska et al. [98], where experimental use of orexin A has been shown to increase heart rate, renal sympathetic activity, catecholamine release, and mean arterial blood pressure. "
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    ABSTRACT: Menopause is characterized by depletion of ovarian follicles, a reduction of ovarian hormones to castrate levels and elevated levels of serum gonadotropins from the anterior pituitary gland. Although this process has significant repercussions throughout the body and affects a large proportion of our society, the neuroendocrine control mechanisms that accompany menopause are poorly understood. This review aims to examine rigorously the most accredited literature to provide an update about our current understanding of the role of the hypothalamic-pituitary axis in the onset of and transition into female reproductive senescence, focusing on the role of some specific neuropeptides in regulating the HPG axis and on their effects on several menopausal symptoms, especially referring to the cardiovascular risk, to open up new horizons for new therapeutic strategies.
    Full-text · Article · May 2012
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