title: Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway.
abstract: Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.
authors.affiliation: a Geriatric Research Education and Clinical Center, Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA.|b Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Hale Z
authors.initials: HZ
authors.lastname: Toklu
authors.affiliation: b Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Scarpace
authors.affiliation: b Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Sakarya
authors.affiliation: a Geriatric Research Education and Clinical Center, Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA.|b Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kirichenko
authors.affiliation: b Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Matheny
authors.affiliation: b Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Bruce
authors.affiliation: c Department of Aging and Geriatric Research, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Christy S
authors.initials: CS
authors.lastname: Carter
authors.affiliation: d Department of Psychiatry, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Drake
authors.initials: D
authors.lastname: Morgan
authors.affiliation: a Geriatric Research Education and Clinical Center, Malcolm Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA.|b Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Tümer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging; D000818:Animals; D060825:Cognitive Dysfunction / Q000209:etiology / Q000517:prevention & control*; D003433:Crosses, Genetic; D003497:Cyclic N-Oxides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002149:Energy Intake / Q000187:drug effects; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D057967:Infusions, Intraventricular; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects*; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D013113:Spin Labels
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D050796:STAT3 Transcription Factor; D013113:Spin Labels; C494088:Stat3 protein, rat; D055372:AMP-Activated Protein Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C001803:tempol
keywords: AMPK; FOXO; SIRT1; STAT3; aging; brain; cerveau; hypothalamus; intracerebroventricular (icv); intracerebroventricular (« icv »); leptin; leptine; obesity; obésité; oxidative stress; p53; stress oxydatif; tempol; vieillissement