title: β1-adrenergic receptor stimulation by agonist Compound 49b restores insulin receptor signal transduction in vivo.
abstract: OBJECTIVE
  Determine whether Compound 49b treatment ameliorates retinal changes due to the lack of β2-adrenergic receptor signaling.
  
  
  METHODS
  Using retinas from 3-month-old β2-adrenergic receptor-deficient mice, we treated mice with our novel β1-/β2-adrenergic receptor agonist, Compound 49b, to assess the effects of adrenergic agonists acting only on β1-adrenergic receptors due to the absence of β2-adrenergic receptors. Western blotting or enzyme-linked immunosorbent assay (ELISA) analyses were performed for β1- and β2-adrenergic receptors, as well as key insulin resistance proteins, including TNF-α, SOCS3, IRS-1(Ser307), and IR(Tyr960). Analyses were also performed on key anti- and proapoptotic proteins: Akt, Bcl-xL, Bax, and caspase 3. Electroretinogram analyses were conducted to assess functional changes, while histological assessment was conducted for changes in retinal thickness.
  
  
  RESULTS
  A 2-month treatment of β2-adrenergic receptor-deficient mice with daily eye drops of 1 mM Compound 49b, a novel β1- and β2-adrenergic receptor agonist, reversed the changes in insulin resistance markers (TNF-α and SOCS3) observed in untreated β2-adrenergic receptor-deficient mice, and concomitantly increased morphological integrity (retinal thickness) and functional responses (electroretinogram amplitude). These results suggest that stimulating β1-adrenergic receptors on retinal endothelial cells or Müller cells can compensate for the loss of β2-adrenergic receptor signaling on Müller cells, restore insulin signal transduction, reduce retinal apoptosis, and enhance retinal function.
  
  
  CONCLUSIONS
  Since our previous studies with β1-adrenergic receptor knockout mice confirmed that the reverse also occurs (β2-adrenergic receptor stimulation can compensate for the loss of β1-adrenergic receptor activity), it appears that increased activity in either of these pathways alone is sufficient to block insulin resistance-based retinal cell apoptosis.
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN.
authors: Youde
authors: Y
authors: Jiang
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN.
authors: Qiuhua
authors: Q
authors: Zhang
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN.
authors: Eun-Ah
authors: EA
authors: Ye
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN ; Department of Anatomy/Neurobiology, University of Tennessee Health Science Center, Memphis, TN ; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN.
authors: Jena J
authors: JJ
authors: Steinle
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004596:Electroretinography; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011972:Receptor, Insulin / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D055504:Insulin Receptor Substrate Proteins; D050505:Mutant Proteins; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin