Activation of hepatic inflammatory pathways by catecholamines is associated with hepatic insulin resistance in male ischemic stroke rats.
Patients who experience acute ischemic stroke may develop hyperglycemia, even in the absence of diabetes. In the current study we determined the effects of acute stroke on hepatic insulin signaling, TNF-α expression, endoplasmic reticulum (ER) stress, the activities of c-Jun N-terminal kinase (JNK), inhibitor κB kinase β (IKK-β), and nuclear factor-κB (NF-κB) pathways. Rats with cerebral ischemia developed higher blood glucose, and insulin levels, and insulin resistance index, as well as hepatic gluconeogenic enzyme expression compared with the sham-treated group. The hepatic TNF-α mRNA and protein levels were elevated in stroke rats in association with increased ER stress, phosphorylation of JNK1/2 and IKK-β proteins, IκB/NF-κB signaling, and phosphorylation of insulin receptor-1 (IRS-1) at serine residue. The basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and AKT proteins was reduced. In addition, acute stroke increased circulating catecholamines in association with hepatic adrenergic signaling activation. After administration of a nonselective β-adrenergic receptor blocker (propranolol) before induction of cerebral ischemic injury, hepatic adrenergic transduction, TNF-α expression, ER stress, and the activation of the JNK1/2, IKK-β, and NF-κB pathways, and serine phosphorylation of IRS-1 were all attenuated. In contrast, the phosphorylated IRS-1 at tyrosine site and AKT levels were partially restored with improved poststroke hyperglycemia and insulin resistance index. These results suggest that acute ischemic stroke can activate proinflammatory pathways in the liver by the catecholamines and is associated with the development of hepatic insulin resistance.
Division of Family Medicine (Y.Y.W.), Division of Endocrinology and Metabolism (S.Y. L., Y.H.C., W.H.H.S.), Department of Medical Research (C.J.C.), Taichung Veterans General Hospital, Taichung, Taiwan; and Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan (Y.Y.W., K.C.T.); and School of Medicine, National Yang Ming University, Taipei, Taiwan (Y.Y.W, S.Y.L., W.H.H.S.).
Ya-Yu
YY
Wang
Shih-Yi
SY
Lin
Yu-Han
YH
Chuang
Wayne Huey-Herng
WH
Sheu
Kwong-Chung
KC
Tung
Chun-Jung
CJ
Chen
D000273:Adipose Tissue / Q000473:pathology; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology*; D002395:Catecholamines / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000473:pathology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D011433:Propranolol / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020521:Stroke / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097382:CD68 Molecule
D000410:Alanine Transaminase; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002395:Catecholamines; D017868:Cyclic AMP-Dependent Protein Kinases; D016207:Cytokines; D007328:Insulin; D011433:Propranolol; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule