Adipose Mitochondrial Biogenesis Is Suppressed in db/db and High-Fat Diet–Fed Mice and Improved by Rosiglitazone

Adipose Mitochondrial Biogenesis Is Suppressed in db/db and High-Fat Diet–Fed Mice and Improved by Rosiglitazone James X. Rong 1 , Yang Qiu 2 3 , Michael K. Hansen 3 , Lei Zhu 3 4 , Vivian Zhang 3 , Mi Xie 1 , Yuji Okamoto 5 , Michael D. Mattie 6 , Hiroyuki Higashiyama 5 , Satoshi Asano 5 , Jay C. Strum 6 and Terence E. Ryan 3 1 High Throughput Biology, Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 2 Cheminformatics, Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 3 Integrative Biology, High Throughput Biology, Discovery Research, GlaxoSmithKline, King of Prussia, Pennsylvania 4 Biomedical Data Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina 5 Tsukuba Research Laboratories, High Throughput Biology, Discovery Research, GlaxoSmithKline, Ibaraki, Japan 6 Department of Quantitative Expression, Genetics Research, GlaxoSmithKline, Research Triangle Park, North Carolina Address correspondence and reprint requests to James X. Rong, High Throughput Biology, Discovery Research, GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC. E-mail: james.x.rong{at}gsk.com Abstract The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator–activated receptor (PPAR) γ agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db , high-fat diet–fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/+ and standard-fat diet–fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1β, PGC-1α, estrogen-relat