Orexins are a pair of hypothalamic neuropeptides involved in sensing and coordinating orchestrated changes in wakefulness, appetite and metabolism1. Defects in orexin signaling results in narcolepsy,a sleep disorder, demonstrating that orexins are vital for sustaining states of conciousness. Consistent with its role in promoting feeding, both orexin KO mice as well as human narcoleptic patients are hypophagic and yet are obese and diabetic. Despite its central role in energy metabolism, it is unclear as to how the regulation is mediated. Investigations focusing on orexin triggered networks revealed it?s close nexus with the master regulator of hypoxia signaling, the Hypoxia Inducible Factor-1 alpha (HIF-1a). Orexin activates HIF-1a to elevate expressions of glucose transporters to enhance glycolysis. Orexin inhibits PDK1, which stimulates PDH activity. Enhanced glycolysis combined with oxidative phosphorylation increase intracellular ATP. Rise in orexin level promotes feeding. Ingested carbohydrates are rapidly converted to glucose, which then inhibits further orexin synthesis. Orexin ramps up HIF-1a mRNA and stabilizes the protein by inhibiting VHL transcription, which encodes a component of E3 ligase complex. Paradoxically, accumulated HIF1-a stabilization fails to induce a classical hypoxic response but generates a metabolic effect that is in stark contrast to that seen in hypoxia. HIF1-alpha dependent metabolic programming in hypoxia directs glycolytic pyruvate into anaerobic glycolysis leading to the production of lactate. Orexin dependent stimulation of HIF-1a, on the other hand, leads to the utilization of pyruvate by oxiadative phosphorylation. In accordance, PDK1 transcript level drops leading to the stimulation of PDH activity in response to orexin. This allows cells to efficiently harvest energy from each molecule of glucose transported. These findings demonstrate how regulation of hunger and consciousness are intimately tied up with the metabolic regulator HIF-1a and how the hypothalamus communicates with peripheral cells and induce metabolic reprogramming. Our results show that signaling by orexin stimulates energy expenditure by enhancing metabolism and perhaps provide a clue as to why human narcolepsy is clinically associated with obesity.
RESEARCH INTERESTS
Sleep, Orexin triggered gene network
signal transduction
narcolepsy
Genome-wide profiling of transcription factors
promoter microarrays
RECENT PUBLICATIONS
Sikder D and Kodadek T., "Neurohormone Orexin stimulates Hypoxia Inducible factor-1 activity." Genes Development, 21 (22):2995-3005, November 2007
Ferdous A, Sikder D, Nalley K, Kodadek T, and Johnston SA, "The role of the proteasomal ATPases and activator Monoubiquitylation in regulating" Genes and Development, 21:112-123, 2007
Sikder D, Johnston SA and Kodadek T, "Widespread, but non-identical, association of proteasomal 19 and 20S proteins with yeast chromatin." J Biol Chem, 281:27346-55, 2006
Page TJ, Sikder D, Yang L, Pluta L, Wolfinger RD, Kodadek T, and Thomas RS., "Genome-wide analysis of HSF1 signaling network reveals a complex transcriptional program involved in cellular adaptation and survival." Mol. Biosystems, 2:627-639, 2006
Xiao X, Yu P, Lim H-S, Sikder D and Kodadek T., "Design of Cell Permeable Transcription factor Mimic" Angew Chem Int Ed Engl., 46:2865-2868, 2007
Sikder D and Kodadek T, "Genomic studies of transcription factor-DNA interactions." Curr Opin Chem Biol., 9:38-45, 2005
Lovett-Racke AE, Rocchini AE, Choy J, Northrop SC, Hussain RZ, Ratts RB, Sikder D and Racke MK, "Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes." Immunity, 21:719-31, 2004
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