J A Manning

Bio: J A Manning is an academic researcher. The author has contributed to research in topics: Fatty acid-binding protein & Fatty acid. The author has an hindex of 1, co-authored 1 publications receiving 101 citations.

Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight Loss

Abstract: Leptin elicits a metabolic response that cannot be explained by its anorectic effects alone. To examine the mechanism underlying leptin9s metabolic actions, we used transcription profiling to identify leptin-regulated genes in ob/ob liver. Leptin was found to specifically repress RNA levels and enzymatic activity of hepatic stearoyl–CoA desaturase-1 (SCD-1), which catalyzes the biosynthesis of monounsaturated fatty acids. Mice lacking SCD-1 were lean and hypermetabolic. ob/ob mice with mutations in SCD-1 were significantly less obese than ob/ob controls and had markedly increased energy expenditure. ob/ob mice with mutations in SCD-1 had histologically normal livers with significantly reduced triglyceride storage and VLDL (very low density lipoprotein) production. These findings suggest that down-regulation of SCD-1 is an important component of leptin9s metabolic actions.

Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling.

Abstract: The intracellular concentration of free unbound acyl-CoA esters is tightly controlled by feedback inhibition of the acyl-CoA synthetase and is buffered by specific acyl-CoA binding proteins. Excessive increases in the concentration are expected to be prevented by conversion into acylcarnitines or by hydrolysis by acyl-CoA hydrolases. Under normal physiological conditions the free cytosolic concentration of acyl-CoA esters will be in the low nanomolar range, and it is unlikely to exceed 200 nM under the most extreme conditions. The fact that acetyl-CoA carboxylase is active during fatty acid synthesis (Ki for acyl-CoA is 5 nM) indicates strongly that the free cytosolic acyl-CoA concentration is below 5 nM under these conditions. Only a limited number of the reported experiments on the effects of acyl-CoA on cellular functions and enzymes have been carried out at low physiological concentrations in the presence of the appropriate acyl-CoA-buffering binding proteins. Re-evaluation of many of the reported effects is therefore urgently required. However, the observations that the ryanodine-senstitive Ca2+-release channel is regulated by long-chain acyl-CoA esters in the presence of a molar excess of acyl-CoA binding protein and that acetyl-CoA carboxylase, the AMP kinase kinase and the Escherichia coli transcription factor FadR are affected by low nanomolar concentrations of acyl-CoA indicate that long-chain acyl-CoA esters can act as regulatory molecules in vivo. This view is further supported by the observation that fatty acids do not repress expression of acetyl-CoA carboxylase or Delta9-desaturase in yeast deficient in acyl-CoA synthetase.

Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production.

Abstract: Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production

Critical Role of stearoyl-CoA desaturase-1 (SCD1) in the Onset of Diet-Induced Hepatic Insulin Resistance

Abstract: Stearoyl-CoA desaturase-1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids from saturated fatty acids. Mice with a targeted disruption of Scd1 gene locus are lean and display increased insulin sensitivity. To examine whether Scd1 activity is required for the development of diet-induced hepatic insulin resistance, we used a sequence-specific antisense oligodeoxynucleotide (ASO) to lower hepatic Scd1 expression in rats and mice with diet-induced insulin resistance. Treatment of rats with Scd1 ASO markedly decreased liver Scd1 expression (approximately 80%) and total Scd activity (approximately 50%) compared with that in rats treated with scrambled ASO (control). Insulin clamp studies revealed severe hepatic insulin resistance in high-fat-fed rats and mice that was completely reversed by 5 days of treatment with Scd1 ASO. The latter treatment decreased glucose production (by approximately 75%), gluconeogenesis, and glycogenolysis. Downregulation of Scd1 also led to increased Akt phosphorylation and marked decreases in the expression of glucose-6-phosphatase (Glc-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Thus, Scd1 is required for the onset of diet-induced hepatic insulin resistance.

The cellular fatty acid binding proteins: aspects of structure, regulation, and function.

Abstract: Publisher Summary This chapter provides a comprehensive overview of the current state of knowledge of the research with particular emphasis on evolving concepts of fatty acid binding proteins (FABP) structure, regulation, and function. Long-chain fatty acids provide the main energy source of most mammalian tissues and also comprise essential components of the structural lipids of cell membranes. The purification of the specific proteins responsible for the low-molecular-weight fatty-acid binding protein activity in different tissues leads to the characterization of three structurally distinct FABP of similar size, each the product of a separate gene. The three cytosolic FABP are generally named according to their tissues of greatest abundance, and comprise liver FABP, intestinal FABP, and heart muscle FABP. A role for the 40-kDa LPM-FABP as a specific cell membrane carrier in the transport of long chain fatty acids into the cells of the liver and possibly other tissues as well is available. The 14- to 15-kDa cytosolic FABPs may function as intracellular acceptors and carriers of long-chain fatty acids and their coenzyme A (CoA) esters, maintaining the ability of the tissues, particularly liver, intestine, heart, and skeletal muscle to utilize fatty acids over wide and acutely varying ranges of flux.