TY - JOUR
T1 - Transcriptional metabolic inflexibility in skeletal muscle among individuals with increasing insulin resistance
AU - Jans, Anneke
AU - Sparks, Lauren M.
AU - Van Hees, Anneke M.J.
AU - Gjelstad, Ingrid M.F.
AU - Tierney, Audrey C.
AU - Risérus, Ulf
AU - Drevon, Christian A.
AU - Roche, Helen M.
AU - Schrauwen, Patrick
AU - Blaak, Ellen E.
PY - 2011/11
Y1 - 2011/11
N2 - Disturbances in skeletal muscle lipid metabolism may play an important role in development of insulin resistance (IR). The aim was to investigate transcriptional control of skeletal muscle fatty acid (FA) metabolism in individuals with the metabolic syndrome (MetS) with varying degrees of insulin sensitivity (S I). 122 individuals with MetS (NCEP-ATP III criteria) at age 35-70 years, BMI 27-38 kg/m 2 were studied (subgroup EU-LIPGENE study). Individuals were divided into quartiles of S I measured during a frequently sampled insulin modified intravenous glucose tolerance test. Skeletal muscle normalized mRNA expression levels of genes important in skeletal muscle FA handling were analyzed with quantitative real-time PCR. The expression of sterol regulatory element binding protein 1c (SREBP1c), acetyl-CoA carboxylase 2 (ACC2), diacylglycerol acyltransferase (DGAT1), and nuclear respiration factor (NRF) was higher in the lowest two quartiles of S I (50th) compared with the highest two quartiles of S I (50th). Interestingly, peroxisome proliferator-activated receptor coactivator 1α (PGC1α), peroxisome proliferator-activated receptor α (PPARα), and muscle carnitine palmitoyl transferase 1b (mCPT1), important for oxidative metabolism, showed a complex mRNA expression profile; levels were lower in both the most insulin sensitive (IS) as well as the most IR individuals. Lipoprotein lipase (LPL) mRNA was reduced in the lowest quartile of S I. Enhanced gene expression of SREBP1c and ACC2 in the IR state suggests a tendency towards FA storage rather than oxidation. From the lower expression of PGC1α, PPARα, and mCPT1 in both the most IS as well as the most IR individuals, it may be speculated that IS subjects do not need to upregulate these genes to have a normal FA oxidation, whereas the most IR individuals are inflexible in upregulating these genes.
AB - Disturbances in skeletal muscle lipid metabolism may play an important role in development of insulin resistance (IR). The aim was to investigate transcriptional control of skeletal muscle fatty acid (FA) metabolism in individuals with the metabolic syndrome (MetS) with varying degrees of insulin sensitivity (S I). 122 individuals with MetS (NCEP-ATP III criteria) at age 35-70 years, BMI 27-38 kg/m 2 were studied (subgroup EU-LIPGENE study). Individuals were divided into quartiles of S I measured during a frequently sampled insulin modified intravenous glucose tolerance test. Skeletal muscle normalized mRNA expression levels of genes important in skeletal muscle FA handling were analyzed with quantitative real-time PCR. The expression of sterol regulatory element binding protein 1c (SREBP1c), acetyl-CoA carboxylase 2 (ACC2), diacylglycerol acyltransferase (DGAT1), and nuclear respiration factor (NRF) was higher in the lowest two quartiles of S I (50th) compared with the highest two quartiles of S I (50th). Interestingly, peroxisome proliferator-activated receptor coactivator 1α (PGC1α), peroxisome proliferator-activated receptor α (PPARα), and muscle carnitine palmitoyl transferase 1b (mCPT1), important for oxidative metabolism, showed a complex mRNA expression profile; levels were lower in both the most insulin sensitive (IS) as well as the most IR individuals. Lipoprotein lipase (LPL) mRNA was reduced in the lowest quartile of S I. Enhanced gene expression of SREBP1c and ACC2 in the IR state suggests a tendency towards FA storage rather than oxidation. From the lower expression of PGC1α, PPARα, and mCPT1 in both the most IS as well as the most IR individuals, it may be speculated that IS subjects do not need to upregulate these genes to have a normal FA oxidation, whereas the most IR individuals are inflexible in upregulating these genes.
UR - http://www.scopus.com/inward/record.url?scp=80055037339&partnerID=8YFLogxK
U2 - 10.1038/oby.2011.149
DO - 10.1038/oby.2011.149
M3 - Article
C2 - 21701566
AN - SCOPUS:80055037339
SN - 1930-7381
VL - 19
SP - 2158
EP - 2166
JO - Obesity
JF - Obesity
IS - 11
ER -
