Cardiovascular effects of leptin and orexins
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.
SourceAvailable from: Teri M Furlong
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ABSTRACT: Background: The hypothesis was that an orexin 2 receptor (OX2R) agonist would prevent sleep-related disordered breathing. Methods: In C57BL/6J (B6) mice, body plethysmography was performed with and without EEG monitoring of state (wakefulness, NREM and REM sleep). Outcome was apnea rate/h during sleep-wake states at baseline and with an intracerebroventricular administration of vehicle, 4 nMol of agonist OBDL, and 4 nMol of an antagonist, TCS OX2 29. Results: A significant reduction (p = 0.035,f = 2.99) in apneas/hour occurred, especially with the agonist. Expressed as a function of the change from baseline, there was a significant difference among groups in Wake (p = 0.03,f = 3.8), NREM (p = 0.003,f = 6.98) and REM (p = 0.03,f = 3.92) with the agonist reducing the rate of apneas during sleep from 29.7 +/- 4.7 (M +/- SEM) to 7.3 +/- 2.4 during sleep (p = 0.001). There was also a reduction in apneas during wakefulness. Administration of the antagonist did not increase event rate over baseline levels. Conclusions: The B6 mouse is a preclinical model of wake-and sleep-disordered breathing, and the orexin receptor agonist at a dose of 4 nMol given intracerebroventricularly will reduce events in sleep and also wakefulness. Published by Elsevier B.V.Respiratory Physiology & Neurobiology 06/2014; 200. DOI:10.1016/j.resp.2014.03.014 · 1.97 Impact Factor
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ABSTRACT: Neurons expressing the leptin receptor (Ob-R) exist within the caudal nucleus of the solitary tract (NTS). Additionally, afferent neurons expressing the Ob-R have been identified within the nodose ganglion and NTS. Furthermore, systemic injections or focal injections of leptin directly into NTS potentiate the response of NTS neurons to carotid chemoreceptor activation. However, the distribution of carotid body afferents in relation to Ob-R containing neurons within NTS is not known. In this study, chemoreceptor afferent fibers were labeled following microinjection of the anterograde tract tracer biotinylated dextran amine (BDA) into the carotid body or petrosal/nodose ganglion of Wistar rats. After a survival period of 10-14 days, the NTS was processed for BDA and Ob-R immunoreactivity. Afferent axons originating in the carotid body were found to project to the lateral (Slt), gelantinosa (Sg), and medial (Sm) subnuclei of the NTS complex. A similar, but more robust distribution of BDA labeled fibers was observed in the NTS complex after injections into the petrosal/nodose ganglion. Carotid body BDA labeled fibers were observed in close apposition to Ob-R immunoreactive neurons in the region of Slt, Sg and Sm. In addition, a small number of carotid body afferents were found to contain both BDA and express Ob-R-like immunoreactivity within the regions of Slt, Sg and Sm. Taken together, these data suggest that leptin may modulate carotid chemoreceptor function not only through direct effects on NTS neurons, but also through a direct effect on carotid body primary afferent fibers that innervate NTS neurons.Peptides 06/2014; DOI:10.1016/j.peptides.2014.05.014 · 2.61 Impact Factor