Journal Article

Alterations in Mouse Hypothalamic Adipokine Gene Expression and Leptin Signaling following Chronic Spinal Cord Injury and with Advanced Age

Bigford, Gregory E., Bracchi-Ricard, Valerie C., Bethea, John R., Nash, Mark S.

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Adipokines - metabolism / Age / Aging / Aging - metabolism / Angiopoietin-like 4 Protein / Angiopoietins - biosynthesis / Animals / Atherosclerosis / Biology / Brain / Cardiovascular diseases / Diabetes / eIF-2 Kinase - biosynthesis / Endoplasmic reticulum / Energy law / Energy metabolism / Eukaryotic Initiation Factor-2 - biosynthesis / Fasting / Fatty acids / Female / Gene expression / Gene Expression Regulation / Genes / Health aspects / Health risks / Homeostasis / House mouse / Hypothalamus / Hypothalamus - metabolism / Inflammation / Injuries / Janus kinase 2 / Kinases / Laboratory animals / Leptin / Leptin - biosynthesis / Medical prognosis / Medicine / Membrane Proteins - biosynthesis / Metabolic disorders / Metabolism / Mice / Mice, Inbred C57BL / Molecular modelling / Mortality / Obesity / Oxidation / Paralysis / Physiological aspects / Physiology / Protein-Serine-Threonine Kinases - biosynthesis / Proteins / Receptors, Leptin - biosynthesis / Resistin - biosynthesis / Risk analysis / Risk factors / Rodents / Signal Transduction / Signaling / Spinal cord injuries / Spinal Cord Injuries - metabolism / Stat3 protein / Suppressor of Cytokine Signaling 3 Protein / Suppressor of Cytokine Signaling Proteins - biosynthesis / Therapeutic applications / Type 2 diabetes