title: Alterations in mouse hypothalamic adipokine gene expression and leptin signaling following chronic spinal cord injury and with advanced age.
abstract: Chronic spinal cord injury (SCI) results in an accelerated trajectory of several cardiovascular disease (CVD) risk factors and related aging characteristics, however the molecular mechanisms that are activated have not been explored. Adipokines and leptin signaling are known to play a critical role in neuro-endocrine regulation of energy metabolism, and are now implicated in central inflammatory processes associated with CVD. Here, we examine hypothalamic adipokine gene expression and leptin signaling in response to chronic spinal cord injury and with advanced age. We demonstrate significant changes in fasting-induced adipose factor (FIAF), resistin (Rstn), long-form leptin receptor (LepRb) and suppressor of cytokine-3 (SOCS3) gene expression following chronic SCI and with advanced age. LepRb and Jak2/stat3 signaling is significantly decreased and the leptin signaling inhibitor SOCS3 is significantly elevated with chronic SCI and advanced age. In addition, we investigate endoplasmic reticulum (ER) stress and activation of the uncoupled protein response (UPR) as a biological hallmark of leptin resistance. We observe the activation of the ER stress/UPR proteins IRE1, PERK, and eIF2alpha, demonstrating leptin resistance in chronic SCI and with advanced age. These findings provide evidence for adipokine-mediated inflammatory responses and leptin resistance as contributing to neuro-endocrine dysfunction and CVD risk following SCI and with advanced age. Understanding the underlying mechanisms contributing to SCI and age related CVD may provide insight that will help direct specific therapeutic interventions.
authors: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America. gbigford@med.miami.edu
authors: Gregory E
authors: GE
authors: Bigford
authors: Valerie C
authors: VC
authors: Bracchi-Ricard
authors: Mark S
authors: MS
authors: Nash
authors: John R
authors: JR
authors: Bethea
mesh_terms: D054392:Adipokines / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000378:metabolism*; D007249:Inflammation; D020738:Leptin / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D054411:Receptors, Leptin / Q000096:biosynthesis; D052243:Resistin / Q000096:biosynthesis; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D019892:eIF-2 Kinase / Q000096:biosynthesis
chemical_list: D054392:Adipokines; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D015852:Eukaryotic Initiation Factor-2; D020738:Leptin; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D054411:Receptors, Leptin; D052243:Resistin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019892:eIF-2 Kinase; C407088:Angptl4 protein, mouse; C491411:Socs3 protein, mouse; C486556:Ern2 protein, mouse