Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance: acute effect of fatty acids

Hoeks, J., Hesselink, M. K. C., Russell, Aaron, Mensink, M., Saris, W. H. M., Mensink, R. P. and Schrauwen, P. 2006, Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance: acute effect of fatty acids, Diabetologia, vol. 49, no. 10, pp. 2419-2426, doi: 10.1007/s00125-006-0369-2.

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Title Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance: acute effect of fatty acids
Author(s) Hoeks, J.
Hesselink, M. K. C.
Russell, AaronORCID iD for Russell, Aaron
Mensink, M.
Saris, W. H. M.
Mensink, R. P.
Schrauwen, P.
Journal name Diabetologia
Volume number 49
Issue number 10
Start page 2419
End page 2426
Publisher Springer-Verlag
Place of publication Heidelberg, Germany
Publication date 2006-10
ISSN 0012-186X
Keyword(s) fatty acids
insulin resistance
lipid metabolism
type 2 diabetes mellitus
Summary Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 (PPARGC1), a coactivator regulating the transcription of genes involved in oxidative metabolism, is downregulated in patients with type 2 diabetes and in their first-degree relatives. Whether this downregulation is a cause or effect of early aberrations in the development of insulin resistance, such as disturbances in fat metabolism, is unknown. We examined whether lipid-induced insulin resistance was associated with downregulation of expression of skeletal muscle genes involved in oxidative metabolism and mitochondrial biogenesis in humans.
Materials and methods Nine healthy lean male subjects underwent a 6-h hyperinsulinaemic–euglycaemic clamp with simultaneous infusion of either a lipid emulsion or glycerol as a control. Blood was sampled at regular time points and muscle biopsies were taken before and after every test. Intramuscular triacylglycerol (IMTG) content was determined by Oil Red O staining and gene expression was measured by quantitative PCR.
Results Lipid infusion resulted in a ∼2.7-fold increase in plasma NEFA levels and a 31±6% decrease in insulin sensitivity (p=0.001). The infusion of lipids resulted in a ∼1.6-fold increase in IMTG (p=0.02), whereas during the clamp with glycerol infusion IMTG tended to decrease to ∼53% of preinfusion levels (p=0.065). Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to ∼61, 77 and ∼52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8-fold (all p<0.05).
Conclusions/interpretation Acute elevation of plasma NEFA levels, leading to muscular fat accumulation and insulin resistance, downregulates PPARGC1A, PPARGC1B and PPARA expression, suggesting that the decrease in PPARGC1 expression observed in the (pre)diabetic state may be the result, rather than the cause of lipid-induced insulin resistance.

Language eng
DOI 10.1007/s00125-006-0369-2
Field of Research 060101 Analytical Biochemistry
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2006, Springer-Verlag
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