title: Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress.
abstract: Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase. The collection of these changes was accompanied by elevated sympathetic tone and prevented by sympathetic suppression. Molecular studies revealed that acute induction of metabolic disorders via brain ER stress was abrogated by NF-κB inhibition in the hypothalamus. Therapeutic experiments further revealed that acute inhibition of brain ER stress with tauroursodeoxycholic acid (TUDCA) partially reversed obesity-associated metabolic and blood pressure disorders. In conclusion, ER stress in the brain represents a mediator of the sympathetic disorders that underlie the development of insulin resistance syndrome and T2D.
authors.affiliation: Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sudarshana
authors.initials: S
authors.lastname: Purkayastha
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.forename: Zaghloul
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D004435:Eating; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D018149:Glucose Intolerance / Q000139:chemically induced; D049452:Green Fluorescent Proteins; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009490:Neurosecretory Systems / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013686:Telemetry; D019284:Thapsigargin / Q000633:toxicity
chemical_list: D007328:Insulin; D016328:NF-kappa B; D049452:Green Fluorescent Proteins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D019284:Thapsigargin