Journal Article

Pioglitazone Induces Mitochondrial Biogenesis in Human Subcutaneous Adipose Tissue In Vivo

Steven R. Smith, George A. Bray, Iwona Bogacka, Hui Xie

2005

Overview

Pioglitazone Induces Mitochondrial Biogenesis in Human Subcutaneous Adipose Tissue In Vivo Iwona Bogacka , Hui Xie , George A. Bray and Steven R. Smith From the Molecular Endocrinology Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana Address correspondence and reprint requests to Iwona Bogacka, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA. E-mail: bogackiu{at}pbrc.edu Abstract Thiazolidenediones such as pioglitazone improve insulin sensitivity in diabetic patients by several mechanisms, including increased uptake and metabolism of free fatty acids in adipose tissue. The purpose of the present study was to determine the effect of pioglitazone on mitochondrial biogenesis and expression of genes involved in fatty acid oxidation in subcutaneous fat. Patients with type 2 diabetes were randomly divided into two groups and treated with placebo or pioglitazone (45 mg/day) for 12 weeks. Mitochodrial DNA copy number and expression of genes involved in mitochondrial biogenesis were quantified by real-time PCR. Pioglitazone treatment significantly increased mitochondrial copy number and expression of factors involved in mitochondrial biogenesis, including peroxisome proliferator–activated receptor (PPAR)-γ coactivator-1α and mitochondrial transcription factor A. Treatment with pioglitazone stimulated the expression of genes in the fatty acid oxidation pathway, including carnitine palmitoyltransferase-1, malonyl-CoA decarboxylase, and medium-chain acyl-CoA dehydrogenase. The expression of PPAR-α, a transcriptional regulator of genes encoding mitochondrial enzymes involved in fatty acid oxidation, was higher after pioglitazone treatment. Finally, the increased mitochondrial copy number and the higher expression of genes involved in fatty acid oxidation in human adipocytes may contribute to the hypolipidemic effects of pioglitazone. ADRB3, adrenergic β-3 receptor CPT-1, carnitine palmitoylotransferase I FPG, fasting plasma glucose MCAD, medium-chain acyl-CoA dehydrogenase MLYCD, malonyl-CoA decarboxylase mtDNA, mitochondrial DNA mtTFA, mitochondrial transcription factor A NRF, nuclear respiratory factor PGC-1α, peroxisome proliferator–activated receptor coactivator-1α PPAR, peroxisome proliferator–activated receptor TZD, thiazolidinedione UCP, uncoupling protein Footnotes I.B. has received grant/research support from Takeda Pharmaceuticals. H.X. has received grant/research support from Takeda Pharmaceuticals. G.A.B. has served on an advisory board of, has received honoraria from, and has received grant/research support from Takeda Pharmaceuticals. S.R.S. has received honoraria/consulting fees and research support from Takeda Pharmaceuticals. Accepted February 17, 2005. Received June 23, 2004. DIABETES

• Publisher: American Diabetes Association
• Subject: Adipose tissue / Adipose Tissue - drug effects / Adipose Tissue - physiology / Adipose tissues / Biological and medical sciences / Body fat / Diabetes. Impaired glucose tolerance / Diabetics / DNA, Mitochondrial - drug effects / DNA, Mitochondrial - genetics / Drug therapy / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Exercise / Gene Expression Regulation - drug effects / Health aspects / Humans / Hypoglycemic Agents - pharmacology / Medical sciences / Mitochondria - drug effects / Mitochondria - physiology / Pioglitazone / Polymerase Chain Reaction / PPAR gamma - genetics / Thiazolidinediones - pharmacology