Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomics to find that obesity-related insulin resistance in skeletal muscle is characterized by excessive beta-oxidation, impaired switching to car...

Previous studies have shown that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a cell-permeable activator of AMP-activated protein kinase, increases the rate of fatty acid oxidation in skeletal muscle of fed rats. The present study investigated the mechanism by which this occurs and, in particular, whether changes in the activity of malonyl-CoA decarboxylase (MCD) and the beta-isoform ...

Insulin resistance in skeletal muscle is present in humans with type 2 diabetes (non-insulin dependent diabetes mellitus) and obesity and in rodents with these disorders. Malonyl CoA is a regulator of carnitine palmitoyl transferase l (CAP I), the enzyme that controls the transfer of long chain fatty acyl CoA into mitochondria, where it is oxidized. In rat skeletal muscle, the formation of malo...

UNLABELLED An increasing body of evidence has revealed that activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK)-activated protein kinase increases fatty acid oxidation by lowering the concentration of malonyl coenzyme A (CoA), an inhibitor of carnitine palmitoyl transferase 1. Studies carried out primarily in skeletal muscle suggest that AMPK modulates the concentration ...

Malonyl-CoA inhibits the carnitine-dependent transport of activated fatty acids into mitochondria by inhibiting the outer carnitine palmitoyltransferase (McGarry et al., 1978). Recent studies in several laboratories have shown that malonyl-CoA is not an ordinary competitive inhibitor of the enzyme. Liver mitochondria from fasted or diabetic rats are less inhibited by malonyl-CoA than are mitoch...

Chalcone and stilbene synthases (CHS and STS) catalyze condensation reactions of p-coumaroyl-CoA and three C(2)-units from malonyl-CoA, but catalyze different cyclization reactions to produce naringenin chalcone and resveratrol, respectively. Condensing activities of wild-type CHS and STS as well as STS-C60S mutant were inhibited by iodoacetamide (Idm) and diethyl pyrophosphate (DPC). DPC also ...

Type 2 diabetes is a disease of metabolic dysregulation involving impaired uptake and utilization of glucose, altered lipid metabolism, accumulation of various lipid species in the circulation and in tissues, and disruption of metabolic signaling pathways that regulate insulin secretion from pancreatic islet -cells. Normal fuel homeostasis involves reciprocal regulation of glucose and lipid cat...

1. The active site of the overt activity of carnitine palmitoyltransferase (CPT I) in rat liver mitochondria was blocked by the self-catalysed formation of the S-carboxypalmitoyl-CoA ester of (-)-carnitine, followed by washing of the mitochondria. CPT I activity in treated mitochondria was inhibited by 90-95%. 2. Binding of [14C]malonyl-CoA to these mitochondria was not inhibited as compared wi...

The kinetics of carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) were examined in mitochondria from rat liver, heart and skeletal muscle as a function of pH over the range 6.8-7.6. In all three tissues raising the pH resulted in a fall in the Km for carnitine, no change in the Km for palmitoyl-CoA or Octanoyl-CoA, and a marked decrease in the inhibitory potency of malonyl-CoA. Studies with...