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Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals.

Consitt LA, Bell JA, Koves TR, Muoio DM, Hulver MW, Haynie KR, Dohm GL, Houmard JA - Diabetes (2010)

Bottom Line: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha).Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels.Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance.

View Article: PubMed Central - PubMed

Affiliation: Department of Exercise and Sport Science, East Carolina University, Greenville, North Carolina, USA. consittl@ecu.edu

ABSTRACT

Objective: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha).

Research design and methods: FAO was studied in HSkMC from lean (BMI 22.4 +/- 0.9 kg/m(2); N = 12) and extremely obese (45.3 +/- 1.4 kg/m(2); N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1alpha expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete ((14)CO(2) production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis.

Results: Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels. PGC-1alpha overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1alpha overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups.

Conclusion: Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance.

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PGC-1α overexpression does not normalize lipid partitioning rates between HSkMC from lean (■) and obese (□) donors. The partitioning of fatty acids between oxidative and storage pathways was evaluated by dividing the rate of oleate esterified into glycerolipid by the rate completely oxidized in response to either 100 μmol/l (A) or 500 μmol/l (B) [14C] oleate in HSkMC from lean (n = 8) and obese (n = 8) donors. Data are means ± SE and significant differences denoted at the P ≤ 0.05 level. *Significant difference between lean and obese for that treatment. †Significant main effect comparing control (β-gal) and PGC-1α overexpression (Ad-PGC-1α) at the respective adenoviral doses. ‡Significant difference between the high and low Ad-PGC-1α doses.
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Figure 4: PGC-1α overexpression does not normalize lipid partitioning rates between HSkMC from lean (■) and obese (□) donors. The partitioning of fatty acids between oxidative and storage pathways was evaluated by dividing the rate of oleate esterified into glycerolipid by the rate completely oxidized in response to either 100 μmol/l (A) or 500 μmol/l (B) [14C] oleate in HSkMC from lean (n = 8) and obese (n = 8) donors. Data are means ± SE and significant differences denoted at the P ≤ 0.05 level. *Significant difference between lean and obese for that treatment. †Significant main effect comparing control (β-gal) and PGC-1α overexpression (Ad-PGC-1α) at the respective adenoviral doses. ‡Significant difference between the high and low Ad-PGC-1α doses.

Mentions: Lipid partitioning was estimated by determining the rate of lipid esterification relative to complete FAO; a higher ratio is indicative of increased partitioning toward storage. Myotubes from obese donors had a higher partitioning index compared with HSkMC from lean donors (P < 0.05) (Fig. 4A and B) regardless of the oleate concentration. Overexpression of PGC-1α at the low dose did not alter this ratio from the control condition, whereas high-dose PGC-1α overexpression (approximately eightfold increase in PGC-1α protein) decreased this ratio under low oleate conditions (P < 0.05) (Fig. 4A).


Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals.

Consitt LA, Bell JA, Koves TR, Muoio DM, Hulver MW, Haynie KR, Dohm GL, Houmard JA - Diabetes (2010)

PGC-1α overexpression does not normalize lipid partitioning rates between HSkMC from lean (■) and obese (□) donors. The partitioning of fatty acids between oxidative and storage pathways was evaluated by dividing the rate of oleate esterified into glycerolipid by the rate completely oxidized in response to either 100 μmol/l (A) or 500 μmol/l (B) [14C] oleate in HSkMC from lean (n = 8) and obese (n = 8) donors. Data are means ± SE and significant differences denoted at the P ≤ 0.05 level. *Significant difference between lean and obese for that treatment. †Significant main effect comparing control (β-gal) and PGC-1α overexpression (Ad-PGC-1α) at the respective adenoviral doses. ‡Significant difference between the high and low Ad-PGC-1α doses.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874701&req=5

Figure 4: PGC-1α overexpression does not normalize lipid partitioning rates between HSkMC from lean (■) and obese (□) donors. The partitioning of fatty acids between oxidative and storage pathways was evaluated by dividing the rate of oleate esterified into glycerolipid by the rate completely oxidized in response to either 100 μmol/l (A) or 500 μmol/l (B) [14C] oleate in HSkMC from lean (n = 8) and obese (n = 8) donors. Data are means ± SE and significant differences denoted at the P ≤ 0.05 level. *Significant difference between lean and obese for that treatment. †Significant main effect comparing control (β-gal) and PGC-1α overexpression (Ad-PGC-1α) at the respective adenoviral doses. ‡Significant difference between the high and low Ad-PGC-1α doses.
Mentions: Lipid partitioning was estimated by determining the rate of lipid esterification relative to complete FAO; a higher ratio is indicative of increased partitioning toward storage. Myotubes from obese donors had a higher partitioning index compared with HSkMC from lean donors (P < 0.05) (Fig. 4A and B) regardless of the oleate concentration. Overexpression of PGC-1α at the low dose did not alter this ratio from the control condition, whereas high-dose PGC-1α overexpression (approximately eightfold increase in PGC-1α protein) decreased this ratio under low oleate conditions (P < 0.05) (Fig. 4A).

Bottom Line: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha).Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels.Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance.

View Article: PubMed Central - PubMed

Affiliation: Department of Exercise and Sport Science, East Carolina University, Greenville, North Carolina, USA. consittl@ecu.edu

ABSTRACT

Objective: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha).

Research design and methods: FAO was studied in HSkMC from lean (BMI 22.4 +/- 0.9 kg/m(2); N = 12) and extremely obese (45.3 +/- 1.4 kg/m(2); N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1alpha expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete ((14)CO(2) production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis.

Results: Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels. PGC-1alpha overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1alpha overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups.

Conclusion: Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance.

Show MeSH
Related in: MedlinePlus