title: Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase glucose metabolism in astrocytes.
abstract: Activation of peroxisome proliferator-activated receptors (PPARs) can regulate brain physiology and provide protection in models of neurological disease; however, neither their exact targets nor mechanisms of action in brain are known. In many cells, PPAR gamma agonists increase glucose uptake and metabolism. Because astrocytes store glucose and provide lactate to neurons on demand, we tested effects of PPAR gamma agonists on astroglial glucose metabolism. Incubation of cortical astrocytes with the PPAR gamma thiazolidinedione (TZD) agonist pioglitazone (Pio) significantly increased glucose consumption in a time- and dose-dependent manner, with maximal increase of 36% observed after 4 h in 30 microm Pio. Pio increased 2-deoxy-glucose uptake because of increased flux through the type 1 glucose transporter. However, at this time point Pio did not increase type 1 glucose transporter expression, nor were its effects blocked by transcriptional or translational inhibitors. Pio also increased astrocyte lactate production as soon as 3 h after incubation. These effects were replicated by other TZDs; however, the order of efficacy (troglitazone > pioglitazone > rosiglitazone) suggests that effects were not mediated via PPAR gamma activation. TZDs increased astrocyte cAMP levels, and their glucose modifying effects were reduced by protein kinase A inhibitors. TZDs inhibited state III respiration in isolated brain mitochondria, whereas in astrocytes they caused mitochondrial membrane hyperpolarization. Pio protected astrocytes against hypoglycemia-induced cell death. Finally, glucose uptake was modified in brain sections prepared from Pio-fed rats. These results demonstrate that TZDs modify astrocyte metabolism and mitochondrial function, which could be beneficial in neurological conditions where glucose availability is reduced.
authors.affiliation: Veterans Affairs Chicago Health Care System West Side Division, Chicago, Illinois, 60680, USA. cdr@uic.edu
authors.forename: Cinzia
authors.initials: C
authors.lastname: Dello Russo
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Gavrilyuk
authors.forename: Guy
authors.initials: G
authors.lastname: Weinberg
authors.forename: Angeles
authors.initials: A
authors.lastname: Almeida
authors.forename: Juan P
authors.initials: JP
authors.lastname: Bolanos
authors.forename: June
authors.initials: J
authors.lastname: Palmer
authors.forename: Dale
authors.initials: D
authors.lastname: Pelligrino
authors.forename: Elena
authors.initials: E
authors.lastname: Galea
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002227:Carbazoles; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006019:Glycolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D013844:Thiazoles / Q000819:agonists* / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D007004:Hypoglycemic Agents; D007211:Indoles; D007773:Lactates; D009004:Monosaccharide Transport Proteins; D011758:Pyrroles; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C057416:KT 5720; C089946:2,4-thiazolidinedione; D005947:Glucose; D000077205:Pioglitazone