Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

被引：68

作者：

Hsiao, Gene ^{[1
]}

Chapman, Justin ^{[4
]}

Ofrecio, Jachelle M. ^{[2
]}

Wilkes, Jason ^{[2
]}

Resnik, Jamie L. ^{[3
]}

Thapar, Divya ^{[2
]}

Subramaniam, Shankar ^{[1
]}

Sears, Dorothy D. ^{[2
]}

机构：

[1] Univ Calif San Diego, Dept Bioengn, San Diego, CA 92103 USA

[2] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA

[3] Univ Calif San Diego, Dept Reprod Med, San Diego, CA 92103 USA

[4] Pfizer Inc, La Jolla, CA USA

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2011年 / 300卷 / 01期

关键词：

thiazolidinedione; insulin resistance; branched-chain amino acids; adipose tissue inflammation; selective peroxisome proliferator-activated receptor modulator; SPPARM; ACTIVATED-RECEPTOR-GAMMA; ADIPOSE-TISSUE; SKELETAL-MUSCLE; MITOCHONDRIAL BIOGENESIS; MICROARRAY DATA; RESISTANCE; FAT; INFLAMMATION; CONTRIBUTES; MECHANISMS;

D O I：

10.1152/ajpendo.00219.2010

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Hsiao G, Chapman J, Ofrecio JM, Wilkes J, Resnik JL, Thapar D, Subramaniam S, Sears DD. Multi-tissue, selective PPAR gamma modulation of insulin sensitivity and metabolic pathways in obese rats. Am J Physiol Endocrinol Metab 300: E164-E174, 2011. First published October 20, 2010; doi:10.1152/ajpendo.00219.2010.-Peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPAR gamma ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPAR gamma ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin-sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPAR gamma ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPAR gamma ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPAR gamma ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization.

引用

页码：E164 / E174

页数：11

共 54 条

[31] Global transcript profiles of fat in monozygotic twins discordant for BMI:: Pathways behind acquired obesity [J].

Pietilainen, Kirsi H. ;

Naukkarinen, Jussi ;

Rissanen, Aila ;

Saharinen, Juha ;

Ellonen, Pekka ;

Keranen, Heli ;

Suomalainen, Anu ;

Gotz, Alexandra ;

Suortti, Tapani ;

Yki-Jarvinen, Hannele ;

Oresic, Matej ;

Kaprio, Jaakko ;

Peltonen, Leena .

PLOS MEDICINE, 2008, 5 (03) :0472-0483

[32]

Poulos S., 2005, ADIPOCYTES, V1, P79

[33] Genome-Wide Occupancy of SREBP1 and Its Partners NFY and SP1 Reveals Novel Functional Roles and Combinatorial Regulation of Distinct Classes of Genes [J].

Reed, Brian D. ;

Charos, Alexandra E. ;

Szekely, Anna M. ;

Weissman, Sherman M. ;

Snyder, Michael .

PLOS GENETICS, 2008, 4 (07)

[34] PPARs and molecular mechanisms of transrepression [J].

Ricote, Mercedes ;

Glass, Christopher K. .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2007, 1771 (08) :926-935

[35] Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone [J].

Rong, James X. ;

Qiu, Yang ;

Hansen, Michael K. ;

Zhu, Lei ;

Zhang, Vivian ;

Xie, Mi ;

Okamoto, Yuji ;

Mattie, Michael D. ;

Higashiyama, Hiroyuki ;

Asano, Satoshi ;

Strum, Jay C. ;

Ryan, Terence E. .

DIABETES, 2007, 56 (07) :1751-1760

[36] Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways [J].

Ryder, JW ;

Bassel-Duby, R ;

Olson, EN ;

Zierath, JR .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (45) :44298-44304

[37] Hematopoietic Cell-Specific Deletion of Toll-like Receptor 4 Ameliorates Hepatic and Adipose Tissue Insulin Resistance in High-Fat-Fed Mice [J].

Saberi, Maziyar ;

Woods, Niels-Bjarne ;

de Luca, Carl ;

Schenk, Simon ;

Lu, Juu Chin ;

Bandyopadhyay, Gautam ;

Verma, Inder M. ;

Olefsky, Jerrold M. .

CELL METABOLISM, 2009, 10 (05) :419-429

[38]

Saenz J, 2006, ORG PROCESS RES DEV, V11, P30

[39] Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization [J].

Sears, D. D. ;

Hsiao, G. ;

Hsiao, A. ;

Yu, J. G. ;

Courtney, C. H. ;

Ofrecio, J. M. ;

Chapman, J. ;

Subramaniam, S. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (44) :18745-18750

[40] Selective modulation of promoter recruitment and transcriptional activity of PPARγ [J].

Sears, Dorothy D. ;

Hsiao, Albert ;

Ofrecio, Jachelle M. ;

Chapman, Justin ;

He, Weimin ;

Olefsky, Jerrold M. .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2007, 364 (03) :515-521

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