Dual effects of fibroblast growth factor 21 on hepatic energy metabolism.

The aim of this study was to investigate the mechanisms by which fibroblast growth factor 21 (FGF21) affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long-day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline; n=6) or recombinant human FGF21 protein (1 mg/kg per day; n=6) for 14 days. FGF21 administration caused a 40% suppression (P<0.05) of hepatic pyruvate dehydrogenase complex (PDC), the rate-limiting step in glucose oxidation, a 34% decrease (P<0.05) in hepatic acetylcarnitine accumulation, an index of reduced PDC flux, a 35% increase (P<0.05) in long-chain acylcarnitine content (an index of flux through ß-oxidation) and a 47% reduction (P<0.05) in hepatic lipid content. These effects were underpinned by increased protein abundance of PD kinase-4 (PDK4, a negative regulator of PDC), the phosphorylated (inhibited) form of acetyl-CoA carboxylase (ACC, a negative regulator of delivery of fatty acids into the mitochondria) and the transcriptional co-regulators of energy metabolism peroxisome proliferator activated receptor gamma co-activator alpha (PGC1α) and sirtuin-1. These findings provide novel mechanistic basis to support the notion that FGF21 exerts profound metabolic benefits in the liver by modulating nutrient flux through both carbohydrate (mediated by a PDK4-mediated suppression of PDC activity) and fat (mediated by deactivation of ACC) metabolism, and therefore may be an attractive target for protection from increased hepatic lipid content and insulin resistance that frequently accompany obesity and diabetes.

AMPK attenuates bupivacaine-induced neurotoxicity.

Bupivacaine has been widely used as a long-acting local anesthetic. However, evidence strongly suggests that bupivacaine causes apoptosis. AMP-activated protein kinase (AMPK) regulates metabolic homeostasis and mediates cellular protection from stress. We hypothesized that AMPK may be cytoprotective in bupivacaine-treated Schwann cells. To explore this, we applied bupivacaine to the RT4-D6P2T Schwann cell line. The expression of phosphorylated AMPK was compared after bupivacaine treatment. Bupivacaine induced cell death in a time- and dose- [50% lethal dose (LD(50)) = 316 microM] dependent manner, and increased expression of phosphorylated AMPK after bupivacaine treatment. Bupivacaine-induced cytotoxicity was attenuated by AICAR (an AMPK activator), whereas compound C (an AMPK inhibitor) enhanced it. The cytoprotective effect of AICAR was reversed in the presence of iodotubercidin, an AICAR inhibitor. Our results suggest that the AMPK pathway may protect Schwann cells from bupivacaine-induced cytotoxicity.

Acetyl-L-carnitine requires phospholipase C-IP3 pathway activation to induce antinociception.

The cellular events involved in acetyl-L-carnitine (ALCAR) analgesia were investigated in the mouse hot plate test. I.c.v. pretreatment with aODNs against the alpha subunit of G(q) and G(11) proteins prevented the analgesia induced by ALCAR (100 mg kg(-1) s.c. twice daily for 7 days). Administration of the phospholipase C (PLC) inhibitors U-73122 and neomycin, as well as the injection of an aODN complementary to the sequence of PLCbeta(1), antagonized the increase of the pain threshold induced by ALCAR. Pretreatment with U-73343, an analogue of U-73112 inactive on PLC, did not modify ALCAR analgesic effect. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or pretreatment with TMB-8, a blocker of Ca(++) release from intracellular stores, the antinociception induced by ALCAR was dose-dependently antagonized. I.c.v. treatment with heparin, an IP(3) receptor antagonist, prevented the increase of pain threshold induced by the investigated compound, analgesia that was restored by co-administration of D-myo-inositol. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitors calphostin C and cheleritryne, resulted in a dose-dependent potentiation of ALCAR antinociception. The administration of PKC activators, such as PMA and PDBu, dose-dependently prevented the ALCAR-induced increase of pain threshold. Neither aODNs nor pharmacological treatments produced any behavioral impairment of mice as revealed by the rota-rod and hole board tests. These results indicate that central ALCAR analgesia in mice requires the activation of the PLC-IP(3) pathway. By contrast, the simultaneous activation of PKC may represent a pathway of negative modulation of ALCAR antinociception.

Effect of L-acetyl carnitine HCl on rat steady-state visual evoked potentials. Comparison with L-carnitine.

L-acetyl carnitine administration increases the amplitude of the steady-state visual evoked potentials (VEPs) obtained with sinusoidal luminance stimulation at 8.4 Hz. This effect was studied with three different doses of L-acetyl carnitine (50, 25, 5 mg/kg) and was compared with the results of injection of similar doses of L-carnitine. The effect is most evident when 50 mg/kg L-acetyl carnitine are administered and has two different time peaks. The second peak of activity showed a dose dependency when 25 mg/kg and 5 mg/kg doses were tested. The effects of L-acetyl carnitine could be depressed by the simultaneous administration of atropine sulfate.

Reduction of ischemia-induced acyl carnitine accumulation by TDGA and its influence on lactate dehydrogenase release in diabetic rat hearts.

The contribution of long-chain acyl carnitine to increase enzyme release during ischemia was investigated both in normal and diabetic rat hearts. 2-Tetradecylglycidic acid (TDGA) was used to inhibit acyl carnitine formation. Isolated working-heart preparations were perfused with glucose (11 mM) and palmitate (0.1 mM) in control and mild ischemic conditions. Ischemia induced lactate dehydrogenase (LDH) release from both normal and diabetic hearts, but the release was higher from the diabetics over a 15-min ischemic period. The ischemia-induced tissue accumulation of long-chain acyl carnitine also was greater in diabetic hearts compared with normal hearts. When TDGA was provided in the perfusate 10 min before the addition of palmitate, levels of acyl carnitine were significantly reduced (by approximately 80%) in the ischemic tissue of both groups of hearts. Similarly, LDH release from ischemic hearts was markedly decreased in the presence of TDGA. A positive correlation was shown between LDH release over the ischemic period and the tissue levels of acyl carnitine at the end of ischemia. Significant improvement in mechanical function with TDGA was only observed in ischemic diabetic hearts. There was absolutely no difference in high-energy compounds under a given perfusion condition, either with or without TDGA, between normal and diabetic hearts. It is concluded that lessening the accumulation of fatty acid intermediates, such as acyl carnitine, may be important to prevent or to limit the loss of sarcolemmal integrity under ischemic conditions, especially in diabetic hearts.