Effect of metformin on bioactive lipid metabolism in insulin-resistant muscle

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   Figure 1

   Mechanism of FFA-induced inhibition of insulin signaling. CD36, fatty acid translocase; FATP1, fatty acid transport protein 1; FABPpm, fatty acid-binding protein (plasma membrane); ACS, acyl-coenzyme A synthetase; LCACoA, long-chain acyl-CoAs; LCAC, long-chain acyl-carnitines; SPT, serine palmitoyltransferase; PPA2, protein phosphatase A2; PAP1/PAP2, phosphatidate phosphatase, isoforms 1 and 2; Akt/PKB, protein kinase B; DAG, diacylglycerol; PKC, protein kinase C; IR, insulin receptor; IRS1, insulin receptor substrate 1; GLUT4, glucotransporter 4; AS160, Akt substrate 160; PI3K, phosphatidylinositol-3-kinase; aPKC, atypical protein kinase C; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated kinase; CPT1, carnitine palmitoyltransferase 1. *Denotes lipids with measured concentration and FSR.
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   Figure 2

   Metformin treatment improves glucose and insulin tolerance and muscle insulin signaling in HFD animals. Panels A and C – plasma glucose during OGTT and IPTT tests respectively. Panels B and D – plasma glucose area under curve (AUC) for OGTT and IPTT tests, respectively. Panel E and F – Akt/PKB phosphotylation at serine 473 and theonine 308, respectively; G and H – AS160 phosphorylation and GLUT4 expression, respectively. Values are mean ± s.d. (n = 8 for each group), P < 0.05 against: a- vs C; *- vs HFD.
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   Figure 3

   The effect of metformin on intracellular uptake and acyl-CoA conversion of fatty acids in in skeletal muscle of HFD-fed animals. Panel A – plasma FFA; B, C – protein and mRNA expression of Cd36, Fatp1 and Fabp pm. D – muscle acyl-CoA content; E and F – protein expression and enzymatic activity of ACS. Values are mean ± s.d. (n = 8 for each group), P < 0.05 against: a- vs C; *- vs HFD.
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   Figure 4

   Metformin promotes mitochondrial channeling of fatty acids in skeletal muscle of HFD-fed animals. Panel A and B – total long-chain acyl-carnitine (LCAC) content and FSR; Panel C and D – mRNA and protein expression of CPT1. Panel E – 16:0-AC to 16:0-CoA ratio (a measure of mitochondrial fatty acids uptake); Panel F – malonyl-CoA content; Panels G and H – mRNA expression and protein phosphorylation of ACC. Values are mean ± s.d. (n = 8 for each group), P < 0.05 against: a- vs C; *- vs HFD.
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   Figure 5

   Metformin inhibits synthesis of Cer and DAG in skeletal muscle of HFD-fed animals. Panels A and B – total ceramide content and C16:0-Cer FSR; Panels C and D mRNA and protein expression of SPT; Panels E and F – total DAG content 16:0/16:0-DAG FSR; Panels G and H – phosphatidic acid phosphatase 2 (PAP2) activity and protein expression. Values are mean ± s.d. (n = 8 for each group), P < 0.05 against: a- vs C; *- vs HFD.
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   Figure 6

   Principal component analysis (PCA) reveals association of 18-carbon acyl-chain length Cer and DAG with insulin resistance measures in HFD-fed animals. Panel A – scores scatter plot for 1st and 2nd PCA components. Arrows and names indicate direction and type and of major variables responsible for group differences. Panel B – loadings scatter plot for 2 first PCA components. The variables grouped in 3 major clusters (encircled) are described in ‘Results’ section.

• © 2017 Society for Endocrinology