astressin-2b and Body-Weight

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

The exacerbation of musculoskeletal pain by stress in humans is modeled by the musculoskeletal hyperalgesia in rodents following a forced swim. We hypothesized that stress-sensitive corticotropin releasing factor (CRF) receptors and transient receptor vanilloid 1 (TRPV1) receptors are responsible for the swim stress-induced musculoskeletal hyperalgesia. We confirmed that a cold swim (26 °C) caused a transient, morphine-sensitive decrease in grip force responses reflecting musculoskeletal hyperalgesia in mice. Pretreatment with the CRF2 receptor antagonist astressin 2B, but not the CRF1 receptor antagonist NBI-35965, attenuated this hyperalgesia. Desensitizing the TRPV1 receptor centrally or peripherally using desensitizing doses of resiniferatoxin (RTX) failed to prevent the musculoskeletal hyperalgesia produced by cold swim. SB-366791, a TRPV1 antagonist, also failed to influence swim-induced hyperalgesia. Together these data indicate that swim stress-induced musculoskeletal hyperalgesia is mediated, in part, by CRF2 receptors but is independent of the TRPV1 receptor.

Topics: Acenaphthenes; Analgesics; Analysis of Variance; Animals; Body Weight; Cold Temperature; Disease Models, Animal; Diterpenes; Female; Hyperalgesia; Mice; Morphine; Muscle Strength; Musculoskeletal Pain; Pain Measurement; Peptide Fragments; Peptides, Cyclic; Reaction Time; Receptors, Corticotropin-Releasing Hormone; Swimming; TRPV Cation Channels