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Structural and Functional Consequences of Mitochondrial Biogenesis in Human Adipocytes in Vitro

Department of Molecular Endocrinology (I.B., B.U., M.M., J.M.G., S.R.S.), Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; and Department of Animal Physiology (I.B.), Faculty of Biology, University of Warmia and Mazury in Olsztyn, 10-718 Olsztyn-Kortowo, Poland

Address all correspondence and requests for reprints to: Iwona Bogacka, Pennington Biomedical Research Center, Department of Molecular Endocrinology, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: iwonab{at}uwm.edu.pl or SmithSR{at}pbrc.edu.

Introduction: Mitochondrial biogenesis is a complex process, and several factors and signaling pathways regulate this process in muscle or brown adipocytes. The aim of the study was to explore pathways affecting mitochondrial biogenesis and fatty acid oxidation (FAO) in human white adipocytes.

Methods: Human preadipocytes obtained from liposuction samples were differentiated in vitro. On the 10th day of differentiation, 4 µM forskolin and 1 µM peroxisome proliferator-activated receptor- (PPAR) agonist (pioglitazone, rosiglitazone, or GW 929) or 10 µM PPAR agonist (WY-14,643) were added to the media for 96 h. Quantitative real-time PCR was used to determine gene expression/mitochondrial copy number and ¹⁴C-labeled palmitate to measure direct energy dissipation.

Results: The treatment of adipocytes with forskolin increased mitochondrial copy number and the expression of genes involved in mitochondrial biogenesis (PPAR coactivator 1 and transcriptional factor A) and fatty acid oxidation (PPAR and medium-chain acyl-coenzyme A dehydrogenase). The end (CO₂) and intermediate products (¹⁴C-labeled acid-soluble products) of FAO were also increased after forskolin treatment. PPAR and PPAR agonists increased mitochondrial copy number, uncoupling protein 1, medium-chain acyl-coenzyme A dehydrogenase, and carnitine palmitoyltransferase 1, but did not change PPAR, PPAR coactivator 1, or transcriptional factor A mRNA levels. FAO was higher after rosiglitazone, GW 929, and WY-14,643 but not after pioglitazone treatment.

Conclusions: Pharmacological activation of the cAMP or PPAR pathway pushes the white adipocyte down the oxidative continuum. The direct energy-dissipating effects could be significant tools to treat obesity and to improve insulin resistance in type 2 diabetic patients by reduction of fat accumulation in adipocytes or by reprogramming fatty acid metabolism.

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