Exercise-induced AMPK activation has been replicated by incubating rat muscle with the AMP-mimetic AICAR (or Z-riboside) (74). In keeping with this notion, perfusion of a rat heart with FFAs and glucose, although it causes an increase in citrate (97), is associated with a decrease rather than an increase in the concentration of malonyl-CoA (6). 280, No. Human acetyl CoA carboxylase 2. We would also predict that it will be found in neural cells in the hypothalamus that contain glucokinase or GLUT-4 glucose transporters. Glucose-induced phosphorylation of the insulin receptor. 3, 1 August 2003 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. Davies S. P., Carling D., Munday M. R., Hardie D. G. Diurinal rhythm of phosphorylation of rat liver acetyl CoA carboxylase by the AMP-activated protein kinase, demonstrated using freeze-clamping. As pictured, an increase in glucose availability would both restrain the increase in glycolysis that it causes and diminish fatty acid oxidation. An interesting, but somewhat more complex, picture is observed when the fuels in excess are ketone bodies. 110, No. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress.”. -dependent C Glucose is a major player in these events. Lipid metabolites and protein kinase C in muscle of insulin-resistant rodents, TG, triglycerides; DAG, diacylglycerol; LCFA-CoA, long-chain fatty acyl-CoA; Altered PKC, altered protein kinase C distribution or activity; GK, Goto-Kakizaki. NIH Circulating glucose in the liver stimulates its uptake. 1, Journal of Medicinal Food, Vol. One of these relates to the fact that CPT I is a different protein in skeletal muscle and liver and that the muscle isoform is more sensitive to inhibition by malonyl-CoA by two orders of magnitude (IC50 0.03 vs. 2.7 mM) (70). How alterations in creatine PO4-to-creatine ratio, which have recently been shown to activate AMPK, fit into this scheme remains to be determined. Effects of high fat diets. The color scheme is as follows: … Although classically thought of as an appetite suppressant by virtue of its effects on the arcuate and perhaps other nuclei in the hypothalamus, leptin has also been demonstrated to increase total body energy expenditure (36) and carbohydrate metabolism (54). Likewise, we (116) have failed to observe an increase in assayable ACC activity in rat soleus muscles incubated with insulin or glucose for 20–30 min despite two- to sixfold increases in malonyl-CoA concentration (Fig. On the other hand, studies with immunopurified ACCβ suggest that the observed changes in whole cell citrate, if they are reflected in cytosol, will cause at least a 1.5- to 2-fold increase in ACC activity (134). One molecule of acetyl-CoA joins with a molecule of bicarbonate, requiring energy rendered from ATP. Jang S. H., Cheesbrough T. M., Kolattukudy P. E. Molecular cloning, nucleotide sequence, and tissue distribution of malonyl-CoA decarboxylase. Leptin expression and action: new experimental paradigms. Taken together, these observations indicate a high evolutionary conservation of this fuel-sensing protein kinase family that responds to nutrient signals in the absence of hormones. A number of lines of evidence suggest an association between sustained elevations in the concentration of malonyl-CoA and insulin resistance (i.e., a less than normal biological effect of insulin) in skeletal muscle. 1, 5 December 2016 | Cogent Food & Agriculture, Vol. 19, No. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. A., Holbert R. I., Colca J. R., Corkey B. E., Ruderman N. B. Malonyl coenzyme A and adiposity in the Dahl salt-sensitive rat: effects of pioglitazone. Still further evidence for an association is a remarkably close correlation (r = 0.95) between increases in whole body respiratory quotient and malonyl-CoA levels in muscle of 48-h-starved rats throughout the first 24 h of refeeding (26). This was achieved by genetic deletion of malonyl CoA decarboxylase (MCD −/−), which degrades malonyl CoA, a potent endogenous inhibitor of the rate-limiting enzyme in mitochondrial … The following characteristics of humans and experimental animals at risk for obesity are supportive of this view: 1) a decreased ability to oxidize fatty acids as reflected by a high respiratory quotient (RQ) (4, 17, 19, 99);2) decreased physical activity (99,103), which would be expected to raise the concentration of malonyl-CoA in muscle; 3) hyperinsulinemia and insulin resistance (in children and some adults) (16, 88); and4) high tissue levels of malonyl-CoA (in the Dahl-S rat, a lean rodent that becomes more obese than a control rat when fed a high fat-high sucrose diet) (62). Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCβ and inhibits both its basal activity and activation by citrate. 15, 10 January 2014 | Expert Review of Endocrinology & Metabolism, Vol. 5, Clinical and Experimental Pharmacology and Physiology, Vol. Essential role of acetyl CoA carboxylase in the glucose-induced insulin secretion in a pancreatic β-cell line. 1). Muoio D. M., Dohm G. L., Fiedorek F. T., Tapscott E. B., Coleman R. A. Leptin directly alters lipid partitioning in skeletal muscle. 1998;9(2-4):295-308. doi: 10.1515/jbcpp.1998.9.2-4.295. AICAR (as the riboside) can be taken up by several cell types and phosphorylated to ZMP, ZDP, and ZTP (48). Malate functions in this scheme as the antiporter for citrate efflux from the mitochondria. As already noted, decreases in assayable ACC activity do not account for the changes in malonyl-CoA in skeletal muscle caused by feeding or starvation (141). ACCβ is regulated by phosphorylation-dephosphorylation [AMP-kinase (AMPK) and phosphatases] and by changes in cytosolic concentration of citrate. See text for details. NLM 1-2, 1 June 2006 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. As first shown by Hardie (47), alterations in AMP levels in intact cells and tissues are associated with reciprocal changes in AMPK and ACC activities. Similar lines of thinking have been put forth to explain how glucose increases the concentration of citrate in the pancreatic β-cell (94, 102) and the heart (41, 113). Cytosolic OAA can be derived from transamination of aspartate with pyruvate and as a product of the ATP CL reaction. 2, 1 December 2002 | American Journal of Physiology-Endocrinology and Metabolism, Vol. Also, in the one investigation in which it was measured (15), no increase in muscle citrate was observed. 277, No. 3.Control of β-isoform of acetyl-CoA carboxylase (ACCβ) activity and malonyl-CoA concentration in skeletal muscle. 77, No. 2, The Journal of Korean Diabetes Association, Vol. The common involvement of cytosolic citrate in both the malonyl-CoA fuel-sensing system and the glucose-fatty acid cycle has led us to hypothesize that an increase in its concentration is not a unique feature of the glucose-fatty acid cycle, but rather a more general signal to the muscle cell that it has an excess of fuel for its immediate needs (116). McCollum Award Lecture, 1995: Diet, lifestyle, and weight maintenance. CL, ATP citrate lyase. It also initiated studies of ACC regulation during exercise and other states in which fatty acid oxidation is altered. Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In addition, it increases fat oxidation in muscle (82, 124) and the pancreatic β-cell (122) and inhibits acetyl-CoA carboxylase in fat cells (7). Studies in which muscle has been made to contract by electrical stimulation of its nerve supply for 5 min have revealed that this decrease in malonyl-CoA (29, 134) is associated with a diminution in ACCβ activity that is evident within seconds and persists for upwards of an hour after the cessation of contraction (134, 140) (Fig. A noteworthy feature of the inhibition of ACCβ when it is phosphorylated by AMPK in rat muscle is that it can occur in the face of substantial increases in whole cell concentrations of both citrate and malate (134). Randle P. J., Garland P. B., Hales C. N., Newsholme E. A., Denton R. M., Pogson C. I. Interactions of metabolism and the physiological role of insulin. 22, No. Diabetes Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University Medical Center, Boston, Massachusetts 02118; and, Endocrine-Metabolism Division, Department of Medicine and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755. Our interpretation of these findings is that ACCβ is responding in these circumstances to an increase in the cytosolic concentration of citrate, which is reflected more closely by an increase in the sum of the whole cell concentrations of citrate and malate than of citrate alone (116). Malonyl CoA hypothesis and insulin resistance in humans The existence of malonyl CoA fuel-sensing and signaling mechanism in humans is suggested by Bavenholm et al. The significance of ketone bodies in fat metabolism. Mitchellhill K. I., Michell B. J., House C. M., Stapleton D., Witters L. A., Kemp B. E. Posttranslational modifications of the 5′-AMP-activated protein kinase beta1 subunit. Recent studies indicate that ACCα and ACCβ are the products of distinct genes and that they have different affinities for their substrate, cytosolic acetyl-CoA (Table 1). 10-12, 21 July 2010 | Diabetic Medicine, Vol. Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653. 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