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Effects of Three Thiazolidinediones on Metabolic Regulation and Cold-Induced Thermogenesis.

ABSTRACT: Insulin resistance is closely associated with metabolic diseases such as type 2 diabetes, dyslipidemia, hypertension and atherosclerosis. Thiazolidinediones (TZDs) have been developed to ameliorate insulin resistance by activation of peroxisome proliferator-activated receptor (PPAR) ?. Although TZDs are synthetic ligands for PPAR?, metabolic outcomes of each TZD are different. Moreover, there are lack of head-to-head comparative studies among TZDs in the aspect of metabolic outcomes. In this study, we analyzed the effects of three TZDs, including lobeglitazone (Lobe), rosiglitazone (Rosi), and pioglitazone (Pio) on metabolic and thermogenic regulation. In adipocytes, Lobe more potently stimulated adipogenesis and insulin-dependent glucose uptake than Rosi and Pio. In the presence of pro-inflammatory stimuli, Lobe efficiently suppressed expressions of pro-inflammatory genes in macrophages and adipocytes. In obese and diabetic db/db mice, Lobe effectively promoted insulin-stimulated glucose uptake and suppressed pro-inflammatory responses in epididymal white adipose tissue (EAT), leading to improve glucose intolerance. Compared to other two TZDs, Lobe enhanced beige adipocyte formation and thermogenic gene expression in inguinal white adipose tissue (IAT) of lean mice, which would be attributable to cold-induced thermogenesis. Collectively, these comparison data suggest that Lobe could relieve insulin resistance and enhance thermogenesis at low-concentration conditions where Rosi and Pio are less effective.

SUBMITTER: Sohn JH

PROVIDER: S-EPMC6199571 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Effects of Three Thiazolidinediones on Metabolic Regulation and Cold-Induced Thermogenesis.

Sohn Jee Hyung JH Kim Jong In JI Jeon Yong Geun YG Park Jeu J Kim Jae Bum JB

Molecules and cells 20181001 10

Insulin resistance is closely associated with metabolic diseases such as type 2 diabetes, dyslipidemia, hypertension and atherosclerosis. Thiazolidinediones (TZDs) have been developed to ameliorate insulin resistance by activation of peroxisome proliferator-activated receptor (PPAR) γ. Although TZDs are synthetic ligands for PPARγ, metabolic outcomes of each TZD are different. Moreover, there are lack of head-to-head comparative studies among TZDs in the aspect of metabolic outcomes. In this stu ...[more]

PMID: 30145862

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Project description:8 fractions for the TMT with file number of 748186_F1 to F8 was used for this section. Protein lysates were extracted from 3 WT and 3 FAM195A KO mice using RIPA lysis buffer. Protein concentration was determined and 25 ug of protein were processed. After trypsin digestion samples were then labelled with TMT reagent. A reverse-phase fractionation spin column was used according to the manufacturers directions to fractionate the sample into 8 fractions. Fractions were injected onto an Orbitrap Fusion Lumos mass spectrometer coupled to an Ultimate 3000 RSLC-Nano liquid chromatography system. The mass spectrometer operated in positive ion mode with a source voltage of 1.6 kV and an ion transfer tube temperature of 275 C. MS scans were acquired at 120,000 resolution in the Orbitrap and top speed mode was used for SPS-MS3 analysis with a cycle time of 2.5 sec. MS2 was performed with CID with a collision energy of 35%. The top 10 fragments were selected for MS3 fragmentation using HCD, with a collision energy of 55%. Raw MS data files were analyzed using Proteome Discoverer v2.2 (Thermo), with peptide identification performed using Sequest HT searching against themouse protein database from UniProt. Fragment and precursor tolerances of 10 ppm and 0.6 Da were specified, and three missed cleavages were allowed. Carbamidomethylation of Cys and TMT labelling of N-termini and Lys side-chains were set as a fixed modification, with oxidation of Met set as a variable modification. Description for sample PCF-JC-2191-07-2020 ( 783251-2) and PCF-JC-2227-07-2020 (787223-4) Differentiated brown adipocytes stably expressing FAM195A-miniTurbo were supplemented with 50 uM biotin (2 h) or left untreated. Cell lysates were extracted in 6 M urea RIPA. Biotinylated proteins were obtained after incubation of lysates with streptavidin beads. Samples were run for 1 cm in a protein gel. The area of the gel containing proteins was submitted for analysis. Gel band samples were digested overnight with trypsin following reduction and alkylation with DTT and iodoacetamide. The samples then underwent solid-phase extraction cleanup with an Oasis HLB plate (Waters) and the resulting samples were injected onto an Orbitrap Fusion Lumos mass spectrometer coupled to an Ultimate 3000 RSLC-Nano liquid chromatography system. Samples were injected onto a 75 um i.d., 75-cm long EasySpray column and eluted with a gradient from 0-28% buffer B over 90 min. Buffer A contained 2% (v/v) ACN and 0.1% formic acid in water, and buffer B contained 80% (v/v) ACN, 10% (v/v) trifluoroethanol, and 0.1% formic acid in water. The mass spectrometer operated in positive ion mode with a source voltage of 1.8 kV and an ion transfer tube temperature of 275 C. MS scans were acquired at 120,000 resolution in the Orbitrap and up to 10 MS/MS spectra were obtained in the ion trap for each full spectrum acquired using higher-energy collisional dissociation (HCD) for ions with charges 2-7. Dynamic exclusion was set for 25 sec after an ion was selected for fragmentation. The Proteomics Core Facility at UTSW performed all proteomic analysis reported.

Dataset Information

Effects of Three Thiazolidinediones on Metabolic Regulation and Cold-Induced Thermogenesis.

Publications

Effects of Three Thiazolidinediones on Metabolic Regulation and Cold-Induced Thermogenesis.

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