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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.
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Abstract |
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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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Introduction |
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Initially, attention was focused on tissues with high oxidative capacity such as skeletal muscle. For example, Petersen et al. (7) showed a 40% reduction in muscle mitochondrial oxidative phosphorylation activity in the elderly that was associated with insulin resistance. Our recent results showed a reduction of mitochondrial copy number (mtDNA) in adipose tissue from diabetic volunteers when compared with healthy controls (3). In the same study, we observed that in vivo treatment with pioglitazone (PIO), a peroxisome proliferator-activated receptor- (PPAR) agonist and commonly used insulin-sensitizing drug, restored diminished mtDNA content to levels observed in nondiabetic controls (3).
A number of reports indicate that PPAR coactivator 1 (PGC-1), highly expressed in brown adipocytes, heart, and skeletal muscle, is a key factor driving mitochondrial biogenesis (8, 9, 10). PGC-1 expression is up-regulated after cold exposure or ß-adrenergic stimulation in brown adipose tissue (BAT) and muscle (11, 12) and increased during exercise in muscle (13). More recent experiments revealed a marked induction of PGC-1 mRNA in the liver during fasting, implying a stimulatory role of PGC-1 in gluconeogenesis and fatty acid oxidation (14, 15).
Although PGC-1 expression is low in white adipose tissue (WAT) compared with muscle and brown fat, the literature suggests a role for PGC-1 in mitochondrial biogenesis and oxidative metabolism in WAT. Semple et al. (16) reported 3-fold lower mRNA level of PGC-1 in sc fat of morbidly obese people. We recently reported that PGC-1 mRNA expression is significantly reduced in WAT obtained from type 2 diabetic subjects compared with nondiabetic controls, and activation of the PPAR by PIO reversed the reduced level of PGC-1 mRNA (3). Ectopic expression of PGC-1 in rodent white adipose cells increased the cellular content of mtDNA and altered the adipocyte phenotype toward an oxidative phenotype including an increase in uncoupling protein 1 (UCP-1) (17). In another study, hyperleptinemia decreased the amount of WAT and increased ß-oxidation, PPAR, and PGC-1 mRNA in WAT (18, 19).
PGC-1 interacts with and coactivates many nuclear (20, 21, 22) and nonnuclear receptors such as nuclear respiratory factors (NRF)-1 and -2 (10) and mitochondrial transcription factor A (mtTFA), which is directly responsible for mtDNA replication and transcription.
Based on our in vivo results (3) we hypothesized that PPAR agonists, some of them commonly used in treatment of type 2 diabetes, might up-regulate mitochondrial biogenesis and FAO in vitro. Additionally, in our current study, we describe the effect of a stimulator of cAMP activity (forskolin) and a PPAR agonist (WY-14,643) on the expression of genes regulating mitochondrial biogenesis and FAO. For this purpose we measured mtDNA copy number and the expression of genes regulating mitochondrial biogenesis (PGC-1 and mtTFA) and FAO [PPAR, medium-chain acyl-coenzyme A dehydrogenase (MCAD), and carnitine palmitoylotransferase 1 (CPT-1)] in human adipocytes cultured in vitro. Furthermore, we assessed the impact of activation of these pathways on the oxidation of fatty acids. The direct energy-dissipating effects of these pathways 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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Materials and Methods |
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Human WAT was obtained from liposuction samples (mixture of abdomen, hips, flanks, thighs, and gynecomastia) from five subjects (three women and two men; mean age, 41.8 ± 11.9 yr; body mass index, 27.9 ± 8.2 kg/m2; range, 22.5–39.1 kg/m2). The participants were healthy according to clinical examination and laboratory tests and did not take any medications. All adipose tissue specimens were obtained under a protocol approved by the Institutional Review Board of the Pennington Biomedical Research Center with informed consent of the patients.
The method for preadipocyte isolation was based on a modification of previously published procedures (23, 24). Briefly, 50–100 ml of tissue was subjected to 0.1% collagenase type I digestion with 1% BSA in PBS. Preadipocytes were grown to 80–90% confluence in stromal medium (DMEM/F-10) supplemented with fetal bovine serum and antibiotics. After 48–72 h, the cells were resuspended at a concentration of 3 x 104 cells/cm2. On the second day, the stromal medium was changed to the differentiation medium (DMEM/F-10, 3% FBS, 33 µM biotin, 17 µM pentothenate, 1 µM PPAR agonist rosiglitazone (ROSI), 100 nM insulin, 1 µM dexamethasone, 0.2 mM 3-isobutyl-1-methylxanthine, 1x penicillin/streptomycin/fungizone) for 3 d. Cells were than changed to adipocyte medium (the same as differentiation medium but without ROSI and 3-isobutyl-1-methylxanthine), and the medium was changed every 3rd day. On the 10th day of differentiation, forskolin (4 µM) (EMD Biosciences, Calbiochem, San Diego, CA), PIO (1 µM) (PPAR agonist; Takeda Pharmaceuticals, Lincolnshire, IL) alone or in combination with T0070907 (1 µM) (PPAR antagonist; Calbiochem), ROSI (1 µM) (PPAR agonist; Cayman Chemical, Ann Arbor, MI), GW 929 (100 nM) (PPAR agonist; Calbiochem), or WY-14,643 (10 µM) (PPAR agonist; Alexis, San Diego, CA) were added to the media for 96 h (media and treatments were changed every 24 h). PPAR agonists and antagonist were prepared in dimethylsulfoxide, and the remaining compounds were diluted in medium. Dimethylsulfoxide or medium was added to control cells (without treatments) to obtain the same concentration as in compound-treated conditions.
RNA and DNA extraction
Total RNA from cultured adipocytes was isolated with Trizol reagent (Invitrogen, Carlsbad, CA), purified with RNeasy columns (QIAGEN, Valencia, CA) and quantified spectrophotometrically. DNA was extracted from the same cells, after degradation of protein and RNA with Trizol, by phenol-chloroform extraction and ethanol precipitation according to the manufacturer’s procedure. The total amount of DNA recovered was determined by spectrophotometry.
Real-time RT-PCR for RNA
Real-time RT-PCR for tested genes was performed using a TaqMan 100Rxn PCR core reagent kit (Applied Biosystems, Roche, Branchburg, NJ) as described previously (3, 25). The sequences of primers, probes, and accession numbers for each gene are listed in Table 1
. All expression data were normalized by dividing the amount of target by the amount of cyclophilin B present as an internal control.
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Relative amounts of nuclear DNA (nDNA) and mtDNA were determined by quantitative real-time PCR as described previously (3). The ratio of mtDNA to nDNA reflects the tissue concentration of mitochondria per cell.
FAO assay
Fat oxidation was measured in differentiated adipocytes after 48 h (three subjects) or 96 h (two subjects) of culture with specific treatments (described above) performed in duplicate. Cells were preincubated with a glucose- and serum-free medium for 90 min, followed by a 4-h incubation with [1-14C]palmitate (NEN Life Science Products, Boston, MA) (2 µCi/ml) and 10 µM nonlabeled (cold) palmitate. Palmitate was coupled to fatty acid-free BSA in a molar ratio 5:1. After incubation, 14CO2 (end product of FAO) and 14C-labeled acid-soluble products (ASPs; water-soluble intermediate metabolites of FAO) were measured according to Muoio et al. (26), with some modifications (27). Briefly, assayed medium was transferred into a 48-well trapping plate. The plate was clamped and sealed, and perchloric acid was injected through a rubber diaphragm into the medium, driving CO2 through a tunnel into an adjacent well where it was trapped in 1 N NaOH. After trapping, medium was spun twice for the measurement of [14C]ASPs. Aliquots of NaOH and medium were transferred into scintillation vials, and radioactivity was measured on a multipurpose scintillation counter (model LS 6500; Beckman Instruments, Fullerton, CA). After assay, cells were placed on ice, washed twice with ice-cold Dulbecco’s PBS, and harvested into 0.05% SDS lysis buffer for subsequent protein measurement. Assays were performed in duplicate, and data were normalized to protein content. Absolute rates of FAO were adjusted for specific activity to account for the dilution of [14C]palmitate with unlabeled palmitate.
Glycerol concentration assay
The concentration of glycerol in media after 48 h of culture of differentiated adipocytes with tested treatments was performed in duplicate using a microanalysis analyzer CMA 600 (CMA Microdialysis AB, Solna, Sweden). Linearity for glycerol assay was 2–500 µmol/liter and adjusted for cellular protein content determined by bicinchoninic acid protein assay (Pierce, Rockford, IL).
Statistical analyses
Results from in vitro experiments are expressed as means ± SE. Given differences between donors, data are presented as a percentage ± SE of appropriate control value (set as 100%). Statistical analyses were performed using Statistica (version 6; StatSoft Inc., Tulsa, OK). Significant differences were established by one-way ANOVA with least significant differences post hoc and assumed as significant if P 
0.05.
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Results |
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To examine the pathways regulating mitochondrial biogenesis and FAO in WAT, we examined an in vitro model of differentiated human adipocytes treated 96 h with a cAMP/protein kinase A (PKA) activator, forskolin or agonists of PPAR and PPAR.
Effect of forskolin
To determine whether forskolin affected mitochondrial biogenesis we measured mtDNA copy number and the expression of genes regulating mitochondrial biogenesis. Four days of treatment of differentiated adipocytes with forskolin significantly increased the mitochondrial copy number (
44% increase; P < 0.01) (Fig 1D) and the expression of genes involved in mitochondrial biogenesis: PGC-1 (2-fold increase; P < 0.0001) (Fig. 1A), mtTFA (50% increase; P < 0.0001) (Fig. 1B), and cytochrome c (Cyt c) (2.5-fold increase; P < 0.0001) (Fig. 1C). Forskolin did not change expression of NRF-1, believed to be involved in mitochondrial biogenesis (data not shown). Additionally, forskolin increased a marker of brown adipocytes, UCP-1 mRNA expression, 6-fold (Fig. 1E). The incubation of adipocytes with forskolin caused a an up-regulation of mRNA expression for PPAR (P < 0.0001) (Fig. 2A) and MCAD (P 0.05) (Fig. 2B), key factors driving FAO in several tissues, but not CPT-1, the enzyme catalyzing entry of fatty acids into the mitochondrial matrix (Fig. 1C).
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PPAR as well as PPAR ligands significantly increased mtDNA copy number (Fig. 1D
) and mRNA for UCP-1 (7- to 40-fold increase) (Fig. 1E). The addition of the PPAR antagonist T0070907 (28) significantly reduced the stimulatory effect of PIO on mtDNA copy number (Fig. 1D). This antagonist given alone did not change mtDNA compared with control (Fig. 2D). Unexpectedly, PPAR agonists did not change mRNA expression for PGC-1, a key factor involved in mitochondrial biogenesis (Fig. 1A), or mitochondrial transcriptional factor A (Fig. 1B). Cyt c mRNA expression was higher after ROSI treatment (P < 0.05) (Fig. 1C) and tended to increase after PIO, GW 929, and WY-14,643 (P = 0.081) (Fig. 1C). The presence of the PPAR antagonist T0070907 (28) in the culture, alone or in combination with PIO, significantly reduced mRNA levels of TFA (P < 0.001) (Fig. 1B) and Cyt c (P < 0.05) (Fig. 1C) but not PGC-1 (Fig. 1A).
The treatment of adipocytes with PPAR (PIO, ROSI, and GW 929) or PPAR (WY-14,643) agonists did not significantly change mRNA expression for PPAR (Fig. 2A). The culture of adipocytes with the specific PPAR antagonist T0070907 alone or in combination with PIO also had no effect on PPAR mRNA level. However, all of the factors (PPAR as well PPAR agonists) markedly and significantly increased mRNA expression for MCAD (Fig. 2B) and CPT-1 (Fig. 2C). The classic PPAR target gene, CPT-1 mRNA, increased about 4-fold with all tested agonists of PPAR (P < 0.0001) (Fig. 2C) and about 2.5-fold after PPAR activation (P < 0.05) (Fig. 2C). The stimulatory effect of the PPAR agonist on CPT-1 and MCAD mRNA levels was significantly smaller than PPAR agonists. Furthermore, the addition of the specific PPAR antagonist T0070907 in combination with PIO abolished the stimulatory effect of PIO on MCAD and CPT-1 mRNA expression (Fig. 2, B and C, respectively). Interestingly, culture of the cells with PPAR antagonist alone also diminished the expression of the MCAD and CPT-1 compared with control. We have chosen MCAD as a marker of mitochondrial FAO capacity to maintain consistency with previously published data (3).
FAO
The end (CO2) and intermediate products (ASPs) of FAO were measured after 48 and 96 h of adipocyte culture with forskolin, PPAR (PIO, ROSI, and GW 929) or PPAR (WY-14,643) agonists. Forskolin markedly increased the level of ASPs after 96 h (3-fold increase) (Fig. 3, A and B) as well as CO2 at the two tested time points (2- to 3-fold increase) (Fig. 3, C and D). PPAR as well PPAR agonists generally did not change ASPs levels after 48 h of incubation but slightly (45–100%) increased after 96 h. The CO2 levels were clearly higher (64–152%) after ROSI, GW 929, and WY-14,643 but not after PIO treatment. This was consistent across the four replicates, each from a different donor. We observed similar patterns in CO2 release after 48 and 96 h of treatment (Fig. 3, A and B).
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Glycerol levels were measured after 48 h of treatment of differentiated adipocytes. Addition of forskolin caused a statistically significant, approximately 4-fold increase in glycerol released to the media (Fig. 4). In contrast, culture of adipocytes with PPAR agonists ( or ) did not change glycerol levels relative to control (Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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pathway in vivo increased mitochondrial number and genes involved in fat oxidation. These changes were concomitant with a clinically significant reduction in blood triglyceride levels. In the absence of histological localization, those earlier studies could not distinguish the emergence/differentiation of quiescent brown adipocytes in the white fat depot from the true remodeling/conversion of a white adipocyte into a more oxidative tan phenotype. Our present studies were undertaken to better understand pathways regulating mitochondrial biogenesis and FAO in human differentiated adipocytes.
We found that forskolin, a well-known activator of the cAMP/PKA pathway, increased mitochondrial copy number measured by real-time PCR. Forskolin also increased the transcription of mitochondrial biogenesis genes (PGC-1 and mtTFA) and nuclear encoded mitochondrial gene Cyt c. PGC-1 is a positive regulator of mitochondrial biogenesis, and its expression is increased after cold exposure, hyperphagia, or adrenergic stimulators affecting the cAMP/PKA pathway in brown adipocytes and muscle (29, 30). PGC-1 can be activated by at least two ways, first by cAMP/PKA cascade activating PGC-1 gene expression and second by activation of the p38 MAPK and/or cAMP/p38 MAPK cascade leading to direct phosphorylation of the PGC-1 protein itself (8). In the present study, we found that forskolin treatment significantly increased expression of the majority of tested genes involved in mitochondrial biogenesis including PGC-1, mtTFA, and Cyt c. UCP-1, a specific marker and key regulator of thermogenesis in BAT, was also increased after forskolin treatment. Many reports suggest that the expression and activity of UCP-1 in BAT is predominantly regulated by the sympathetic system via stimulation of ß-adrenergic receptors (31). The increase in UCP-1 expression in our experiments was accompanied by an increase in FAO. Our results showed that forskolin induces the expression of several genes regulating mitochondrial FAO in WAT as observed in other previously described tissues (31). We observed higher expression of PPAR and MCAD but not CPT-1 after forskolin treatment. Additionally, we found markedly higher FAO measured after 48 and 96 h.
We observed a 3.5-fold higher level of glycerol released from adipocytes cultured in the presence of forskolin but no effect of forskolin on expression of the fatty acid transporter FAT/CD36. This indicates that forskolin affects triglyceride stores rather than the import of fatty acids from the extracellular space. Summarizing, the effect of forskolin on mitochondrial biogenesis and FAO in human differentiated adipocytes is strong and similar to that previously reported in rodent brown adipocytes and muscle (9, 32).
In contrast to forskolin, which exhibited a direct and robust stimulatory effect on mitochondrial biogenesis/FAO pathways, the effect of PPAR agonist on mitochondrial biogenesis and FAO is subtly different in the present study. Our results showed that all three tested PPAR agonists significantly increased mtDNA but had a smaller effect on Cyt c and no effect on PGC-1 and mtTFA, factors implicated in mitochondrial replication. In contrast to forskolin, the treatment of cells with a PPAR antagonist alone (28) or in combination with PIO did not change PGC-1 mRNA expression but significantly diminished TFA and Cyt c mRNA levels. These in vitro results are only partially consistent with our recently published data in vivo showing that long-term activation of PPAR by PIO in type 2 diabetic patients significantly increased mtDNA copy number and the expression of genes involved in mitochondrial biogenesis (PGC-1 and mtTFA but not NRF-1) (3). PIO also had a stimulatory effect on the expression of genes involved in fatty acid transport and ß-oxidation; those are classically thought of as PPAR targets (3). PIO did not change energy expenditure or substrate oxidations as measured by indirect calorimetry (33). One interpretation of our in vitro results is the possibility of reprogramming of white fat cells into an intermediate fat-oxidizing phenotype, i.e. tan or brownish adipocyte. Furthermore, adipose tissue contributes to whole-body energy at rest, albeit only minimally compared with the lean tissue. This may explain the differences between our results and whole-body energy expenditure and fat metabolism. It has been reported that PPAR activators [thiazolidinediones (TZDs) and non-TZD agonists] increase mitochondrial biogenesis, FAO, and white adipocyte remodeling in rodents (31, 34, 35, 36). Recently, Wilson-Fritch et al. (35) demonstrated a stimulatory effect of ROSI on mitochondrial biogenesis and remodeling of WAT with concomitant 30% increase of FAO and oxygen consumption in adipocytes isolated from mice. They observed a 2-fold increase in mitochondrial mass and a higher expression of mitochondrial proteins involved in fatty acid transport and oxidation (35); the mechanisms responsible for these described processes remain to be explored. Although Wilson-Fritch et al. (35) predicted only that PGC-1 could play a role in mitochondrial biogenesis, they did not report the gene expression or protein level for this key regulator. In another study performed in rodents, PPAR activation up-regulated UCP-1 and other thermogenic genes (e.g. PGC-1) mRNA expression but without an increase in whole-body energy expenditure (31). Higher energy expenditure after non-TZD PPAR agonist treatment occurred only after ß-adrenergic stimulation (31).
In the present study, the higher mtDNA copy number and increased expression of genes involved in fatty acid transport/ß-oxidation had a similar pattern for three tested PPAR agonists. However, these PPAR agonists did not affect FAO in the same way as determined by the levels of end and intermediate products. We found a clear increase (about 100%) in ASPs and CO2 production determined after 48 or 96 h of incubation for ROSI and GW 929 but not for PIO (all are PPAR agonists). The addition of PIO did not change CO2 levels after 48 or 96 h, although ASP concentration was about 50% higher after 96 h. This observation suggests that although activation of PPAR receptors by PIO and ROSI cause similar changes in body weight and fat remodeling, they have divergent actions on energy dissipation; this may depend upon coactivator recruitment (37, 38). Interestingly, specific activation of PPAR by ROSI and GW increased levels of intermediate and end products of FAO but did not change PPAR mRNA expression, as we found in vivo. We can only predict that activity of PPAR, a key factor driving FAO in several tissues, could be changed in our study not by TZDs but by higher expression of lipolysis products. It has been recently shown that lipoprotein lipase generates PPAR ligands in endothelial cells (39). Several reports indicate a stimulatory effect of PPAR inducers on lipoprotein lipase activity in other tissues (25). The question of why PIO increases expression of genes driving the transport of fatty acids into mitochondria (CPT-1) and the first step of FAO (MCAD), but has no effect on FAO, remains unresolved. Another important question is why PIO and ROSI, both TZDs/PPAR compounds, differentially regulate FAO.
PPAR activation increased the expression of mRNA for UCP-1 in agreement with our previous in vivo results and many others (31, 35, 40, 41). A functional PPAR response element has been found within the UCP-1 promoter (42), and PPAR agonists promote differentiation in BAT as well as in WAT. UCP-1 is induced in both tissues by TZDs in rodents. The cells expressing UCP-1 were described as newly created brown adipocytes. This is not possible in our fully differentiated adipocytes, suggesting plasticity of white adipocytes into tan adipocytes. The enhanced expression of this brown-specific gene UCP-1 was also observed after exogenous insertion of PGC-1 into human adipocytes (41). In our study we demonstrated higher mtDNA copy number and UCP-1 mRNA level, but PGC-1 mRNA did not change. The possible explanation for higher mtDNA copy number and no effect on PGC-1 mRNA expression could be involvement of additional PPAR ligand-dependent cascades regulating nuclear-encoded mitochondrial genes or directly phosphorylating PGC-1 protein, not gene expression (for review see Ref.8). The limitation of the study was measurement of only gene expression and FAO products. We did not determine protein content.
The studies presented herein demonstrate, in fully differentiated adipocytes, that pharmacological activation of the cAMP or PPAR pathway pushes the white adipocyte down the oxidative continuum. This is consonant with earlier studies that genetically modify adipocytes to alter the oxidative phenotype in similar cells (41, 43). The importance of this observation lies in the clinic, where the pharmacological activation of these pathways is known to improve the features of the metabolic syndrome (33, 44). This suggests that the progress of an adipocyte along an oxidative pathway might play a key role in the genesis of the metabolic syndrome.
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Acknowledgments |
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Footnotes |
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First Published Online October 4, 2005
Abbreviations: ASP, Acid-soluble products; BAT, brown adipose tissue; CPT-1, carnitine palmitoyltransferase 1; Cyt c, cytochrome c; FAO, fatty acid oxidation; MCAD, medium-chain acyl-coenzyme A dehydrogenase; mtDNA, mitochondrial DNA; mtTFA, mitochondrial transcription factor A; NRF, nuclear respiratory factor; PGC, PPAR coactivator 1; PIO, pioglitazone; PKA, protein kinase A; PPAR, peroxisome proliferator-activated receptor; ROSI, rosiglitazone; TZD, thiazolidinedione; UCP-1, uncoupling protein 1; WAT, white adipose tissue.
Received May 9, 2005.
Accepted September 23, 2005.
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