Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model

Butterick, Tammy A.; Nixon, Joshua P.; Billington, Charles J.; Kotz, Catherine M.

doi:10.1016/j.neulet.2012.07.002

Cited by 51 publications

(51 citation statements)

References 48 publications

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“…Evidence strongly links development of AD and PD with oxidative stress and mitochondrial dysfunction in the brain (Agostinho et al, 2010; Ferreiro et al, 2012; Niranjan, 2013). In recent in vitro and in vivo studies, we and others have shown that orexin is neuroprotective, reducing neuronal damage caused by ischemia or oxidative insult in hypothalamic, hippocampal, and cortical tissue (Butterick et al, 2012; Sokolowska et al, 2012; Yuan et al, 2011). While the mechanism is not fully defined, orexin appears to increase resistance to oxidative stress by upregulation of hypoxia-inducible factor 1 alpha (HIF-1α) (Butterick et al, 2013; Feng et al, 2014; Sikder and Kodadek, 2007; Yuan et al, 2011).…”

Section: Discussionmentioning

confidence: 92%

Sleep disorders, obesity, and aging: The role of orexin

Nixon

Mavanji

Butterick

et al. 2015

Ageing Research Reviews

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112

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The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of orexin receptor agonist, and naturally-occurring models in which orexin responsiveness varies by individual. We next explore rodent models of orexin in aging, presenting evidence that orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of orexin in human obesity, sleep, and aging. We include discussion of orexin loss in narcolepsy and potential importance of orexin in insomnia, correlations between animal and human studies of age-related decline, and evidence for orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of orexin in neurodegenerative disease. We conclude that orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when orexin signaling is disrupted or lost.

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Section: Discussionmentioning

confidence: 92%

Sleep disorders, obesity, and aging: The role of orexin

Nixon

Mavanji

Butterick

et al. 2015

Ageing Research Reviews

Self Cite

112

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“…Work with these animal models has clearly defined a direct link between orexin signaling and neuromodulation of SPA; however, the cellular signaling pathways through which orexin mediates SPA and obesity resistance still remain largely unknown [9,38]. We present here evidence from multiple in vitro investigations, including data from our ongoing work and that from other non-orexin focused rodent models, to delineate potential mechanisms through which orexin might affect obesity resistance.…”

Section: Orexin and Obesity Resistancementioning

confidence: 99%

“…While increases in HIF-1α are usually associated with hypoxia, OXA induction of HIF-1α occurs in normal, non-hypoxic hypothalamic tissue [70]. OXA has been shown to be neuroprotective in cerebral cortex and in hypothalamic cell culture following oxidative stressors [71,38], potentially through activation of HIF-1α. Recent studies have shown that in conjunction with MAPK, PGC-1α is important in regulating HIF-1α expression [72,62,73,61].…”

Section: Orexin-mediated Signaling and Energy Balancementioning

confidence: 99%

“…We and others have linked OXA to energy metabolism, showing that OXA induces HIF-1α expression in hypothalamic tissue in vitro (Figure 1), and that this results in increased ATP production via oxidative phosphorylation [74,70,38] In separate rodent studies, mice with the neuron-specific loss of the HIF-1α inhibitor asparaginyl hydroxylase factor (FIH) had reduced body weight and were protected against high-fat-diet-induced weight gain [75]. Additionally, mice lacking functional HIF-1α and HIF-2α proteins in arcuate nucleus pro-opiomelanocortin (POMC) neurons (POMC/HIFβ mice) have impaired energy expenditure, hyperphagia, and increased fat mass [76].…”

Section: Orexin-mediated Signaling and Energy Balancementioning

confidence: 99%

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Orexin: Pathways to obesity resistance?

Butterick

Billington

Kotz

et al. 2013

Rev Endocr Metab Disord

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Obesity has increased in prevalence worldwide, attributed in part to the influences of an obesity-promoting environment and genetic factors. While obesity and overweight increasingly seem to be the norm, there remain individuals who resist obesity. We present here an overview of data supporting the idea that hypothalamic neuropeptide orexin A (OXA; hypocretin 1) may be a key component of brain mechanisms underlying obesity resistance. Prior work with models of obesity and obesity resistance in rodents has shown that increased orexin and/or orexin sensitivity is correlated with elevated spontaneous physical activity (SPA), and that orexin-induced SPA contributes to obesity resistance via increased non-exercise activity thermogenesis (NEAT). However, central hypothalamic orexin signaling mechanisms that regulate SPA remain undefined. Our ongoing studies and work of others support the hypothesis that one such mechanism may be upregulation of a hypoxia-inducible factor 1 alpha (HIF-1α)-dependent pathway, suggesting that orexin may promote obesity resistance both by increasing SPA and by influencing the metabolic state of orexin-responsive hypothalamic neurons. We discuss potential mechanisms based on both animal and in vitro pharmacological studies, in the context of elucidating potential molecular targets for obesity prevention and therapy.

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“…At 80 -90% confluence, cells were synchronized overnight in serum-free medium and treated with human recombinant orexin A or B (0, 10 and 100 nM) (Interchim, Montlucon, France) for 24 h. Untreated cells were used as control. The dose and duration of treatments were chosen on the basis of pilot and previous published experiments (12,62,63). QM7 cells were washed twice with phosphate-buffered saline (PBS 1ϫ) and incubated for 12 h in medium with brefeldin A (0.3 g/ml), and lysates and medium were subjected to immunoblot analysis.…”

Section: Methodsmentioning

confidence: 99%

Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics

Lassiter¹,

Greene²,

Piekarski³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Orexin A and B, orexigenic peptides produced primarily by the lateral hypothalamus that signal through two G protein-coupled receptors, orexin receptors 1/2, have been implicated in the regulation of several physiological processes in mammals. In avian (nonmammalian vertebrates) species; however, the physiological roles of orexin are not well defined. Here, we provide novel evidence that not only is orexin and its related receptors 1/2 (ORXR1/2) expressed in chicken muscle tissue and quail muscle (QM7) cell line, orexin appears to be a secretory protein in QM7 cells. In vitro administration of recombinant orexin A and B (rORX-A and B) differentially regulated prepro-orexin expression in a dose-dependent manner with up-regulation for rORX-A (P < 0.05) and downregulation for rORX-B (P < 0.05) in QM7 cells. While both peptides upregulated ORXR1 expression, only a high dose of rORX-B decreased the expression of ORXR2 (P < 0.05). The presence of orexin and its related receptors and the regulation of its own system in avian muscle cells indicate that orexin may have autocrine, paracrine, and/or endocrine roles. rORXs differentially regulated mitochondrial dynamics network. While rORX-A significantly induced the expression of mitochondrial fission-related genes (DNM1, MTFP1, MTFR1), rORX-B increased the expression of mitofusin 2, OPA1, and OMA1 genes that are involved in mitochondrial fusion. Concomitant with these changes, rORXs differentially regulated the expression of several mitochondrial metabolic genes (av-UCP, av-ANT, Ski, and NRF-1) and their related transcriptional regulators (PPARγ, PPARα, PGC-1α, PGC-1β, and FoxO-1) without affecting ATP synthesis. Taken together, our data represent the first evidence of the presence and secretion of orexin system in the muscle of nonmammalian species and its role in mitochondrial fusion and fission, probably through mitochondrial-related genes and their related transcription factors.

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Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model

Cited by 51 publications

References 48 publications

Sleep disorders, obesity, and aging: The role of orexin

Sleep disorders, obesity, and aging: The role of orexin

Orexin: Pathways to obesity resistance?

Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics

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