The PPAR α / γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat.
- Authors
- Wallenius, Kristina; Kjellstedt, Ann; Thalén, Pia; Löfgren, Lars; Oakes, Nicholas D
- Year
- 2013
- Journal
- PPAR research
- PMID
- 24285952
- DOI
- 10.1155/2013/305347
- PMCID
- PMC3826326
lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR) α/γ agonist, tesaglitazar, 3 μ mol/kg/day for 3 weeks. Whole body glucose disposal rate (R d ) and hepatic glucose output (HGO) were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,(3)H]glucose. Indices of tissue specific glucose utilization (R g ') were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-(3)H]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-(13)C]glucose, 2-deoxy-D-[U-(14)C]glucose, [U-(14)C]palmitate, and [9,10-(3)H]-(R)-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of R d compared to obese controls. This involved increased insulin stimulation of R g ' in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover (R fa ), and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or R fa compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats.
Peripheral glucose disposal (R d) and hepatic glucose output (HGO) in Lean, Obese and Tesaglitazar groups of Zucker rats. Data points represent mean ± SE (n = 4-5).
Whole body effects of insulin, under basal and hyperinsulinemic clamp conditions: suppression of plasma FFA and stimulation of glucose disposal rate R d′ ( = “average” tissue utilization rate) in Lean, Obese, and Tesaglitazar groups of Zucker rats. Data points represent means ± SE (n = 5–7).
In vivo glucose utilization rate (R g′) in red quadriceps muscle as a function of plasma insulin levels under basal and hyperinsulinemic clamp conditions in Lean, Obese, and Tesaglitazar groups. Data points represent means ± SE (n = 5–7).
Whole body turnover and tissue specific utilization rates of glucose and FFA. Glucose and FFA flux data are shown in the left and right hand panels, respectively, under basal (open histograms) and hyperinsulinemic clamp (closed histograms) conditions. Mean ± SEM (n = 6-7). *P < 0.01, **P < 0.01, and ***P < 0.001 versus Obese basal state. † P < 0.05, †† P < 0.01 insulin effect in Obese versus Lean (based on Clamp-Basal differences). ‡ P < 0.05, ‡‡ P < 0.01, and ‡‡‡ P < 0.001 insulin effect in Tesaglitazar (Tesa) versus Obese (based on Clamp-Basal differences).
| Name | Type |
|---|---|
| 12C-glucose local | drug |
| 13C-glucose | drug |
| 14C-2-deoxyglucose local | drug |
| 14C-2DG local | drug |
| 14C-labelled anion local | drug |
| 14C-labelled lipids local | drug |
| 14C-labelled metabolites local | drug |
| 2-bromopalmitate local | drug |
| 2-deoxy-D-[2,6-3H]glucose local | drug |
| 2-deoxy-D-[U-14C] glucose local | drug |
| 2-deoxyglucose local | drug |
| 2DG local | drug |
| 3H-2DG local | drug |
| 3H2O local | drug |
| 3H-glucose local | drug |
| 3H-labelled metabolites local | drug |
| 3H-R-BrP local | drug |
| Acacb | gene |
| acetic acid | drug |
| acetic anhydride local | drug |
| Acipimox local | drug |
| albumin-palmitate-fatty acid tracer complex local | drug |
| aldonitrile penta acetate local | drug |
| animal models | cohort |
| antiatherogenic effects local | phenotype |
| apoCIII levels local | phenotype |
| Ba(OH)2 local | drug |
| Blood glucose control local | phenotype |
| c^ local | phenotype |
| Carboxymethyl cellulose local | drug |
| cardiovascular disease | phenotype |
| centrally obese/hypertriglyceridemic nondiabetic humans local | cohort |
| cerebellum | anatomy |
| CO2 | drug |
| control subjects | cohort |
| c P local | phenotype |
| Cyp4a | gene |
| D-[3,3H]glucose local | drug |
| Defective insulin regulation of metabolism local | phenotype |
| Diaphragm local | phenotype |
| dinitrophenol local | drug |
| D-(U-13C) glucose local | drug |
| dyslipidemia | phenotype |
| dyslipidemias local | phenotype |
| EC50 local | phenotype |
| ectopic lipid accumulation local | phenotype |
| Ectopic lipid accumulation local | phenotype |
| esterified fatty acids local | drug |
| ethyl acetate | drug |
| fa/fa Zucker rat local | cohort |
| fatty acids | drug |
| FFA | drug |
| FFA local | phenotype |
| FFA clearance local | phenotype |
| FFA exchange local | phenotype |
| FFA oxidation local | phenotype |
| FFA oxidation capacity local | phenotype |
| FFA utilization local | phenotype |
| fibrate class local | drug |
| food intake | phenotype |
| free fatty acids (FFA) local | drug |
| GIR local | phenotype |
| glucose | drug |
| Glucose infusion rate local | phenotype |
| glucose lowering | phenotype |
| glucose metabolism | phenotype |
| Glucose tolerance test | phenotype |
| Glucose turnover | phenotype |
| glucose utilization local | phenotype |
| Glucose utilization rate local | phenotype |
| glycogen local | drug |
| Glycogen mass local | phenotype |
| glycogen synthesis | phenotype |
| glycogen synthesis rates local | phenotype |
| habitually hyperphagic/hyperinsulinemic animals local | cohort |
| heart | anatomy |
| heart local | phenotype |
| hepatic glucose output | phenotype |
| hepatic glucose output (HGO) local | phenotype |
| Hepatic insulin sensitization local | phenotype |
| hepatic TG content local | phenotype |
| hepatic TG secretion local | phenotype |
| hepatic triglycerides (hepatic TG) local | drug |
| heptane local | drug |
| Human insulin local | drug |
| hydroxylamine local | drug |
| hyperglycemia | phenotype |
| hyperinsulinemia local | drug |
| hyperinsulinemia | phenotype |
| I local | phenotype |
| impaired fatty acid oxidation capacity local | phenotype |
| impaired glucose control local | phenotype |
| impaired metabolic flexibility local | phenotype |
| impaired switching of fatty acid and glucose utilization local | phenotype |
| Impaired tissue FFA flux control local | phenotype |
| Improved insulin mediated glucose control local | phenotype |
| Inactin local | drug |
| inflammation | phenotype |
| insulin | drug |
| Insulin mediated switching of fuel utilization local | phenotype |
| insulin-mediated switching of glucose and fatty acid utilization local | phenotype |
| insulin resistance | phenotype |
| insulin resistant humans local | cohort |
| Insulin resistant phenotype local | phenotype |
| Insulin responsiveness local | phenotype |
| insulin sensitivity | phenotype |
| insulin stimulated glucose uptake local | phenotype |
| insulin stimulated oxidative glucose disposal local | phenotype |
| insulin suppression of hepatic glucose output local | phenotype |
| Isoglycemia local | phenotype |
| isopropanol | drug |
| K fa local | phenotype |
| lean | phenotype |
| Lean local | cohort |
| Lean animals local | cohort |
| lean body mass | phenotype |
| lean control animals local | cohort |
| Lean group local | cohort |
| lean Zucker rat local | cohort |
| lean Zucker rats local | cohort |
| Lean Zucker rats local | cohort |
| Lean Zuckers local | cohort |
| lipid control local | phenotype |
| lipid metabolism | phenotype |
| lipid tolerance local | phenotype |
| liquid nitrogen | drug |
| liver | anatomy |
| meal induced FFA lowering local | phenotype |
| metabolic flexibility local | phenotype |
| Metabolic flexibility local | phenotype |
| metabolic inflexibility local | phenotype |
| Metabolic Switching local | phenotype |
| methyl-tert-butyl ether local | drug |
| Microvette CB300 local | drug |
| Na citrate local | drug |
| neutral lipids local | drug |
| NH2 columns local | drug |
| nonoxidative FFA disposal local | phenotype |
| Obese local | cohort |
| Obese animals local | cohort |
| Obese group local | cohort |
| obese/insulin resistant subjects local | cohort |
| Obese rat local | cohort |
| obese Zucker local | cohort |
| Obese Zucker local | cohort |
| obese Zucker rat local | cohort |
| Obese Zucker rat local | cohort |
| obese Zucker rats local | cohort |
| Obese Zucker rats local | cohort |
| obesity | phenotype |
| ob/ob mice | cohort |
| Optiphase Hisafe III local | drug |
| overnight fasting FFAs local | phenotype |
| oxidative metabolism local | phenotype |
| palmitic acid | drug |
| Patients with type 2 diabetes local | cohort |
| Peripheral insulin action local | phenotype |
| plasma | anatomy |
| plasma FFA flux local | phenotype |
| plasma FFA level local | phenotype |
| Plasma FFA levels local | phenotype |
| plasma FFA oxidation local | phenotype |
| Plasma free fatty acids local | phenotype |
| plasma free fatty acids (FFA) local | drug |
| plasma TG levels local | phenotype |
| polar lipids local | drug |
| polar metabolites local | drug |
| Postprandial state local | phenotype |
| potassium EDTA local | drug |
| PPARA | gene |
| PPARG | gene |
| PPARα | gene |
| PPARα agonist local | drug |
| PPARγ | gene |
| PPARγ agonist local | drug |
| pyridine | drug |
| rats | cohort |
| R d local | phenotype |
| R d′ local | phenotype |
| R^d local | phenotype |
| R f* local | phenotype |
| R fa local | phenotype |
| R fs local | phenotype |
| R g′ local | phenotype |
| RG local | phenotype |
| R gly local | phenotype |
| rodent chow local | drug |
| saline | drug |
| scintillant local | drug |
| serum creatinine local | phenotype |
| skeletal muscle local | phenotype |
| Skeletal muscle | cohort |
| Skeletal muscle local | phenotype |
| skeletal muscle fatty acid oxidation capacity local | phenotype |
| skeletal muscle FFA flux local | phenotype |
| skeletal muscle glucose uptake local | phenotype |
| Stimulation of glucose uptake in skeletal muscle local | phenotype |
| Study 1 local | cohort |
| Study 2 local | cohort |
| Study 3 local | cohort |
| sulphuric acid local | drug |
| Suppression of fatty acid availability local | phenotype |
| Suppression of hepatic glucose production local | phenotype |
| tesaglitazar | drug |
| Tesaglitazar group local | cohort |
| Tesaglitazar-treated obese Zucker rats local | cohort |
| thiazolidinedione local | drug |
| thiazolidinediones | drug |
| thiobutabarbital local | drug |
| thiobutabarbital sodium salt local | drug |
| thiobutarbital local | drug |
| Thiobutarbital local | drug |
| Tissue-specific glucose utilization rate local | phenotype |
| tracers local | drug |
| triglycerides | phenotype |
| TTR local | phenotype |
| TTRna local | phenotype |
| type 2 diabetes | phenotype |
| very low density lipoprotein triglycerides (VLDL TG) local | drug |
| VLDL TG production local | phenotype |
| water | drug |
| weight gain | phenotype |
| White fat local | anatomy |
| White fat local | phenotype |
| whole body fatty acid oxidation local | phenotype |
| Whole body glucose disposal local | phenotype |
| Whole Body Glucose Disposal local | phenotype |
| Whole body insulin action local | phenotype |
| whole body insulin sensitization local | phenotype |
| Whole body Rd′ local | phenotype |
| Wy-14,643 | drug |
| YSI 2700 glucose analyzer local | drug |
| ZnSO4 local | drug |
| Zucker rat local | cohort |
| Zucker rats local | cohort |
| Zuckers local | cohort |
| β-oxidation machinery local | phenotype |
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In this knowledge base
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| Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans. | 2015 | 25516156 |
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