title: Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes.
abstract: OBJECTIVE
  Orexin A (OXA) modulates body weight, food intake and energy expenditure. In vitro, OXA increases PPARγ (also known as PPARG) expression and inhibits lipolysis, suggesting direct regulation of lipid metabolism. Here, we characterise the metabolic effects and mechanisms of OXA action in adipocytes.
  
  
  METHODS
  Isolated rat adipocytes and differentiated murine 3T3-L1 adipocytes were exposed to OXA in the presence or absence of phosphoinositide 3-kinase (PI3K) inhibitors. Pparγ expression was silenced using small interfering RNA. Glucose uptake, GLUT4 translocation, phosphatidylinositol (3,4,5)-trisphosphate production, lipogenesis, lipolysis, and adiponectin secretion were measured. Adiponectin plasma levels were determined in rats treated with OXA for 4 weeks.
  
  
  RESULTS
  OXA PI3K-dependently stimulated active glucose uptake by translocating the glucose transporter GLUT4 from cytoplasm into the plasma membrane. OXA increased cellular triacylglycerol content via PI3K. Cellular triacylglycerol accumulation resulted from increased lipogenesis as well as from a decrease of lipolysis. Adiponectin levels in chow- and high-fat diet-fed rats treated chronically with OXA were increased. OXA stimulated adiponectin expression and secretion in adipocytes. Both pharmacological blockade of peroxisome proliferator-activated receptor γ (PPARγ) activity or silencing Pparγ expression prevented OXA from stimulating triacylglycerol accumulation and adiponectin production.
  
  
  CONCLUSIONS
  Our study demonstrates that OXA stimulates glucose uptake in adipocytes and that the evolved energy is stored as lipids. OXA increases lipogenesis, inhibits lipolysis and stimulates the secretion of adiponectin. These effects are conferred via PI3K and PPARγ2. Overall, OXA's effects on lipids and adiponectin secretion resemble that of insulin sensitisers, suggesting a potential relevance of this peptide in metabolic disorders.
authors.affiliation: Department of Hepatology and Gastroenterology and Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Skrzypski
authors.forename: T
authors.initials: T
authors.lastname: T Le
authors.forename: P
authors.initials: P
authors.lastname: Kaczmarek
authors.forename: E
authors.initials: E
authors.lastname: Pruszynska-Oszmalek
authors.forename: P
authors.initials: P
authors.lastname: Pietrzak
authors.forename: D
authors.initials: D
authors.lastname: Szczepankiewicz
authors.forename: P A
authors.initials: PA
authors.lastname: Kolodziejski
authors.forename: M
authors.initials: M
authors.lastname: Sassek
authors.forename: A
authors.initials: A
authors.lastname: Arafat
authors.forename: B
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: K W
authors.initials: KW
authors.lastname: Nowak
authors.forename: M Z
authors.initials: MZ
authors.lastname: Strowski
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D000068797:Orexins; D051381:Rats; D017208:Rats, Wistar
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins; D005947:Glucose