The neurohormone orexin stimulates hypoxia-inducible factor-1 activity.
Orexin A and Orexin B (also known as hypocretins) are neuropeptides that bind two related G-coupled protein receptors (OXR1 and OXR2) and thus induce wakefulness, food consumption, and locomotion. Conversely, deletion of the orexin gene in mice produces a condition similar to canine and human narcolepsy. Despite the central importance of the orexin system in regulating wakefulness and feeding behavior, little is known about the downstream signaling mechanisms that achieve these effects. In this study, genomics techniques are used to probe this question and reveal that orexin activates the hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor whose pathogenic role in stimulating angiogenesis in hypoxic tumors has been the focus of intense investigation. Orexin-stimulated HIF-1 activity is due to both increased HIF-1alpha gene transcription and a down-regulation of von Hippel-Lindau (VHL), the E3 ubiquitin ligase that mediates the turnover of HIF-1 via the ubiquitin-proteasome pathway. Orexin-mediated activation of HIF-1 results in increased glucose uptake and higher glycolytic activity, as expected from studies of hypoxic cells. However, orexin receptor-expressing cells somehow override the HIF-1-mediated preference for funneling pyruvate into anaerobic glycolysis and instead favor ATP production through the tricarboxylic acid cycle and oxidative phosphorylation. These findings implicate HIF-1 as an important transcription factor in the hormone-mediated regulation of hunger and wakefulness.
Sikder
Devanjan
D
Division of Translational Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9185, USA.
Kodadek
Thomas
T
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003035:Cobalt / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000166:cytology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology; D019344:Lactic Acid / Q000032:analysis; D049409:Luciferases, Firefly / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D064446:Orexin Receptors; D000068797:Orexins; D009924:Organ Culture Techniques; D010957:Plasmids; D011506:Proteins / Q000378:metabolism; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000032:analysis; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D016895:Culture Media, Serum-Free; C000596229:HCRT protein, human; C497459:Hcrtr1 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C419777:OXR1 protein, human; D064446:Orexin Receptors; D000068797:Orexins; D011506:Proteins; D018013:Receptors, Neuropeptide; D019344:Lactic Acid; D003035:Cobalt; D000255:Adenosine Triphosphate; D049409:Luciferases, Firefly; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; C018021:cobaltous chloride; D005947:Glucose