title: Endothelin regulates intermittent hypoxia-induced lipolytic remodelling of adipose tissue and phosphorylation of hormone-sensitive lipase.
abstract: Obstructive sleep apnoea syndrome is characterized by repetitive episodes of upper airway collapse during sleep resulting in chronic intermittent hypoxia (IH). Obstructive sleep apnoea syndrome, through IH, promotes cardiovascular and metabolic disorders. Endothelin-1 (ET-1) secretion is upregulated by IH, and is able to modulate adipocyte metabolism. Therefore, the present study aimed to characterize the role of ET-1 in the metabolic consequences of IH on adipose tissue in vivo and in vitro. Wistar rats were submitted to 14 days of IH-cycles (30 s of 21% FiO2 and 30 s of 5% FiO2 ; 8 h day(-1) ) or normoxia (air-air cycles) and were treated or not with bosentan, a dual type A and B endothelin receptor (ETA-R and ETB-R) antagonist. Bosentan treatment decreased plasma free fatty acid and triglyceride levels, and inhibited IH-induced lipolysis in adipose tissue. Moreover, IH induced a 2-fold increase in ET-1 transcription and ETA-R expression in adipose tissue that was reversed by bosentan. In 3T3-L1 adipocytes, ET-1 upregulated its own and its ETA-R transcription and this effect was abolished by bosentan. Moreover, ET-1 induced glycerol release and inhibited insulin-induced glucose uptake. Bosentan and BQ123 inhibited these effects. Bosentan also reversed the ET-1-induced phosphorylation of hormone-sensitive lipase (HSL) on Ser(660) . Finally, ET-1-induced lipolysis and HSL phosphorylation were also observed under hypoxia. Altogether, these data suggest that ET-1 is involved in IH-induced lipolysis in Wistar rats, and that upregulation of ET-1 production and ETA-R expression by ET-1 itself under IH could amplify its effects. Moreover, ET-1-induced lipolysis could be mediated through ETA-R and activation of HSL by Ser(660) phosphorylation.
authors.affiliation: Université Grenoble Alpes, HP2, Grenoble, France.|INSERM, HP2, U1042, Grenoble, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Briançon-Marjollet
authors.affiliation: Université Grenoble Alpes, HP2, Grenoble, France.|INSERM, HP2, U1042, Grenoble, France.|CHU Grenoble, Departement of Biochemistry, Toxicology and Pharmacology, Biology Pole, Grenoble, France.|Present address: Department of Metabolic Biochemistry, La Pitié Salpêtrière-Charles Foix University Hospital (AP-HP), Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Monneret
authors.affiliation: Université Grenoble Alpes, HP2, Grenoble, France.|INSERM, HP2, U1042, Grenoble, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Henri
authors.affiliation: CHU Grenoble, Departement of Biochemistry, Toxicology and Pharmacology, Biology Pole, Grenoble, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Hazane-Puch
authors.affiliation: Université Grenoble Alpes, HP2, Grenoble, France.|INSERM, HP2, U1042, Grenoble, France.|CHU Grenoble, EFCR Laboratory, Thorax and vessels pole, Grenoble, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pepin
authors.affiliation: Université Grenoble Alpes, HP2, Grenoble, France.|INSERM, HP2, U1042, Grenoble, France.|CHU Grenoble, Departement of Biochemistry, Toxicology and Pharmacology, Biology Pole, Grenoble, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Faure
authors.affiliation: Université Grenoble Alpes, HP2, Grenoble, France.|INSERM, HP2, U1042, Grenoble, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Godin-Ribuot
mesh_terms: D016475:3T3 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000097:blood; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D008066:Lipolysis; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D002787:Sterol Esterase / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D005227:Fatty Acids; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014280:Triglycerides; D002787:Sterol Esterase; D000077300:Bosentan