astressin-2b and Hypoxia

Our objective was to investigate the mechanisms by which the endogenous CRHR2 in white adipose tissue (WAT) regulates metabolic activities associated with lipogenesis and lipolysis under continuous exposure to hypoxia. We found that hypobaric hypoxia at a simulated altitude of 5000 m significantly reduced the body weight, food intake, and WAT mass of rats. Hypoxia also accelerated lipolysis and suppressed lipogenesis in WAT. Pretreatment with astressin 2B, a selective CRHR2 antagonist, partly but significantly attenuated the hypoxia-induced reductions in body weight and WAT mass by blocking the cAMP-protein kinase A (PKA)-hormone-sensitive lipase (HSL)/perilipin signalling pathway. Astressin 2B treatment failed to attenuate hypoxia induced lipogenic inhibition. In conclusion, activation of endogenous WAT Ucn2/3 autocrine/paracrine pathway was involved in hypoxia induced lipolysis via CRHR2 - cAMP-PKA signalling pathway. This study provides the novel understanding of local CRHR2 signaling pathway playing important role in WAT loss and lipid metabolism under hypoxia.

Topics: Adipocytes; Adipose Tissue, White; Adiposity; Altitude; Animals; Body Weight; Cell Size; Corticotropin-Releasing Hormone; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Fatty Acids; Feeding Behavior; Gene Expression Regulation; Hypoxia; Lipogenesis; Lipolysis; Male; Oxidation-Reduction; Peptide Fragments; Peptides, Cyclic; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Signal Transduction; Triglycerides

Urocortin-1 (UCN1) exerts protective effects on hypoxia/reoxygenation injury in the heart. Serum- and glucocorticoid- responsive kinase-1 (SGK1), a serine-threonine kinase, has been shown to be crucial for cardiomyocyte survival. The purpose of the present study was to investigate whether SGK1 is involved in UCN1-induced cardioprotection.. Cardiomyocytes were obtained from neonatal rats and used as a model to investigate UCN1 regulation of SGK1. Specific small interfering RNA targeting SGK1 was used to knock down SGK1 expression. The messenger RNA (mRNA) level of SGK1 was measured using quantitative real time reverse transcription polymerase chain reaction, and the protein levels of SGK1 and phosphorylated SGK1 were determined using Western blot analysis.. SGK1 knockdown attenuated the protective effects of UCN1 against hypoxia/reoxygenation injury in cardiomyocytes. Treatment of cardiomyocytes with UCN1 stimulated SGK1 mRNA and protein expression and time-dependently increased phosphorylated SGK1 level. These effects were completely reversed with corticotrophin-releasing hormone receptor type 2 antagonist. Adenylate cyclase and protein kinase A inhibitors abolished the stimulatory effect of UCN1 on SGK1 expression. SGK1 phosphorylation induced by UCN1 was blocked by phosphorinositide-3-kinase inhibitor.. SGK1 is involved in the cardioprotective effects of UCN1 in cardiomyocytes. UCN1 stimulates SGK1 phosphorylation via the phosphorinositide-3-kinase signalling pathway and it induces SGK1 expression via the adenylate cyclase/protein kinase A pathway.

Topics: Animals; Animals, Newborn; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Chromones; Enzyme Inhibitors; Flavonoids; Gene Knockdown Techniques; Hypoxia; Immediate-Early Proteins; Isoquinolines; Models, Animal; Morpholines; Myocytes, Cardiac; Peptide Fragments; Peptides, Cyclic; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; Real-Time Polymerase Chain Reaction; Receptors, Corticotropin-Releasing Hormone; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Sulfonamides; Urocortins