Article

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

ABSTRACT

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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    • "Expression of OX2R is observed in the amygdala, BST, PVT, DR, VTA, and LDT/PPT (Lu et al., 2000; Marcus et al., 2001; Mieda et al., 2011). Many studies using OX2R −/− mice have suggested important physiological roles of OX2R in the maintenance of wakefulness states (Hondo et al., 2010; Sakurai and Mieda, 2011) and the regulation of metabolic states and feeding behavior (Funato et al., 2009). "
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    ABSTRACT: Neuropeptides orexin A and orexin B, which are exclusively produced by neurons in the lateral hypothalamic area, play an important role in the regulation of a wide range of behaviors and homeostatic processes, including regulation of sleep/wakefulness states and energy homeostasis. The orexin system has close anatomical and functional relationships with systems that regulate the autonomic nervous system, emotion, mood, the reward system, and sleep/wakefulness states. Recent pharmacological studies using selective antagonists have suggested that orexin receptor-1 (OX1R) is involved in physiological processes that regulate emotion, the reward system, and autonomic nervous system. Here, we examined Ox1r−/− mice with a comprehensive behavioral test battery to screen additional OX1R functions. Ox1r−/− mice showed increased anxiety-like behavior, altered depression-like behavior, slightly decreased spontaneous locomotor activity, reduced social interaction, increased startle response, and decreased prepulse inhibition. These results suggest that OX1R plays roles in social behavior and sensory motor gating in addition to roles in mood and anxiety.
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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 makes 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.
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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. "
    [Show abstract] [Hide abstract]
    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.
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