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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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Effect of PGC-1α overexpression on fatty acid incorporation in HSkMC from lean (■) and obese (□) donors. HSkMC cultured from lean (n = 8) and obese (n = 8) donors were incubated with either 100 μmol/l (A, C, and E) or 500 μmol/l (B, D, and F) [14C] oleate, and 14C-labeled incorporation into glycerolipid (A and B), TAG (C and D), and DAG (E and F) was determined. Data are expressed as 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 3: Effect of PGC-1α overexpression on fatty acid incorporation in HSkMC from lean (■) and obese (□) donors. HSkMC cultured from lean (n = 8) and obese (n = 8) donors were incubated with either 100 μmol/l (A, C, and E) or 500 μmol/l (B, D, and F) [14C] oleate, and 14C-labeled incorporation into glycerolipid (A and B), TAG (C and D), and DAG (E and F) was determined. Data are expressed as 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: Oleate incorporation into glycerolipid, TAG, and DAG pools are presented in Fig. 3. Control cells (β-gal) from obese individuals had a greater rate of oleate incorporation into the glycerolipid pool in response to low (∼64%) and high (∼42%) oleate concentrations (Fig. 3A and B). Cells from obese individuals, regardless of treatment, consistently incorporated more lipids into the glycerolipid pool compared with HSkMC from lean subjects (Fig. 3A and B). PGC-1α overexpression increased esterification into the glycerolipid pool at both concentrations of oleate in both groups of subjects.


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)

Effect of PGC-1α overexpression on fatty acid incorporation in HSkMC from lean (■) and obese (□) donors. HSkMC cultured from lean (n = 8) and obese (n = 8) donors were incubated with either 100 μmol/l (A, C, and E) or 500 μmol/l (B, D, and F) [14C] oleate, and 14C-labeled incorporation into glycerolipid (A and B), TAG (C and D), and DAG (E and F) was determined. Data are expressed as 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

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

Figure 3: Effect of PGC-1α overexpression on fatty acid incorporation in HSkMC from lean (■) and obese (□) donors. HSkMC cultured from lean (n = 8) and obese (n = 8) donors were incubated with either 100 μmol/l (A, C, and E) or 500 μmol/l (B, D, and F) [14C] oleate, and 14C-labeled incorporation into glycerolipid (A and B), TAG (C and D), and DAG (E and F) was determined. Data are expressed as 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: Oleate incorporation into glycerolipid, TAG, and DAG pools are presented in Fig. 3. Control cells (β-gal) from obese individuals had a greater rate of oleate incorporation into the glycerolipid pool in response to low (∼64%) and high (∼42%) oleate concentrations (Fig. 3A and B). Cells from obese individuals, regardless of treatment, consistently incorporated more lipids into the glycerolipid pool compared with HSkMC from lean subjects (Fig. 3A and B). PGC-1α overexpression increased esterification into the glycerolipid pool at both concentrations of oleate in both groups of subjects.

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