Enhanced Orexin Receptor-2 Signaling Prevents Diet-Induced Obesity and Improves Leptin Sensitivity

Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Cell metabolism (Impact Factor: 17.57). 02/2009; 9(1):64-76. DOI: 10.1016/j.cmet.2008.10.010
Source: PubMed


The hypothalamic orexin neuropeptide acutely promotes appetite, yet orexin deficiency in humans and mice is associated with obesity. Prolonged effects of increased orexin signaling upon energy homeostasis have not been fully characterized. Here, we examine the metabolic effects of orexin gain of function utilizing genetic and pharmacologic techniques in mice. Transgenic orexin overexpression confers resistance to high-fat diet-induced obesity and insulin insensitivity by promoting energy expenditure and reducing consumption. Genetic studies indicate that orexin receptor-2 (OX2R), rather than OX1R signaling, predominantly mediates this phenotype. Likewise, prolonged central administration of an OX2R-selective peptide agonist inhibits diet-induced obesity. While orexin overexpression enhances the anorectic-catabolic effects of central leptin administration, obese leptin-deficient mice are completely resistant to the metabolic effects of orexin overexpression or OX2R agonist infusion. We conclude that enhanced orexin-OX2R signaling confers resistance to diet-induced features of the metabolic syndrome through negative energy homeostasis and improved leptin sensitivity.

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    • "The synergistic relationship between leptin and orexin is indicated by the fact that orexin levels are lowered when leptin signaling is disrupted, even in a state of obesity (Cai et al., 2000; Yamanaka et al., 2003). Furthermore, orexin overexpression improves leptin sensitivity; a phenomenon that may be involved in suppressing palatable food intake and weight gain (Funato et al., 2009). Clearly, the interrelationship between orexin neurons and leptin is complex and merits further investigation. "
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    ABSTRACT: Initially implicated in the regulation of feeding, orexins/hypocretins are now acknowledged to play a major role in the control of a wide variety of biological processes, such as sleep, energy expenditure, pain, cardiovascular function and neuroendocrine regulation, a feature that make them one of the most pleiotropic families of hypothalamic neuropeptides. While the orexigenic effect of orexins is well described, their central effects on energy expenditure and particularly on brown adipose tissue (BAT) thermogenesis are not totally unraveled. Better understanding of these actions and their possible interrelationship with other hypothalamic systems controlling thermogenesis, such as AMP-activated protein kinase (AMPK) and endoplasmic reticulum (ER) stress, will help to clarify the exact role and pathophysiological relevance of these neuropeptides have on energy balance. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 07/2015; DOI:10.1016/j.mce.2015.07.022 · 4.41 Impact Factor
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    • "Indeed, initially the pivotal role of orexins in short-term feeding was well documented (Sakurai et al., 1998; Dube et al., 1999; B€ ackeberg et al., 2002; Thorpe and Kotz, 2005; Xu et al., 2013). Other evidence linked orexins to metabolic regulation and thermogenesis (Kukkonen et al., 2002; Monda et al., 2004; Funato et al., 2009; Kukkonen, 2013), stress response (Huang et al., 2010; Gerashchenko et al., 2011; Kukkonen, 2013), circadian rhythms (Deboer et al., 2004; Pekala et al., 2011), the regulation of sleep/wakefulness (Gerashchenko et al., 2001; Inutsuka and Yamanaka, 2013; Mieda et al., 2013; de Lecea and Huertra, 2014), memory processing (Akbari et al., 2008; Selbach et al., 2010), pathogenesis of Alzheimer disease (Kang et al., 2009), and epilepsy (Doreulee et al., 2010). It was also demonstrated that orexins modulate arousal: specifically, rodents treated with orexins spend more time awake (Hagan et al., 1999; Piper et al., 2000), and manifest increased locomotor activity (Alexandre et al., 2013). "
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    • "In addition, it has been demonstrated that sleep deprivation may contribute to obesity through modulating plasma levels of leptin (Mullington et al. 2003). Also, the lack of orexin, a hypothalamic wakefulness-inducing neuropeptide (Sakurai et al. 1998), affects sleep, feeding and metabolism (Adamantidis and de Lecea 2008) and is associated with increased likelihood of developing obesity (Funato et al. 2009). Narcolepsy, when patients suffer from extreme daytime sleepiness due to the loss of orexin-producing neurons (Tsujino and Sakurai 2013), has also been linked with increased body mass and obesity (Kotagal et al. 2004). "
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    ABSTRACT: While the significance of obesity as a serious health problem is well recognized, little is known about whether and how biometerological factors and biorhythms causally contribute to obesity. Obesity is often associated with altered seasonal and daily rhythmicity in food intake, metabolism and adipose tissue function. Environmental stimuli affect both seasonal and daily rhythms, and the latter are under additional control of internal molecular oscillators, or body clocks. Modifications of clock genes in animals and changes to normal daily rhythms in humans (as in shift work and sleep deprivation) result in metabolic dysregulation that favours weight gain. Here, we briefly review the potential links between biorhythms and obesity in humans.
    International Journal of Biometeorology 07/2014; 59(4). DOI:10.1007/s00484-014-0871-z · 3.25 Impact Factor
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