Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ghrelin, an orexigenic hormone, directly activates neuropeptide (NPY) neurons in the hypothalamic arcuate nucleus (ARC), and thereby stimulates food intake. The hypothalamic level of AMP-activated protein kinase (AMPK), an intracellular energy sensor, is activated by peripheral and central administration of ghrelin. We examined whether ghrelin regulates AMPK activity in NPY neurons of the ARC. Single neurons were isolated from the ARC and cytosolic Ca(2+) concentration ([Ca(2+)](i)) was measured by fura-2 microfluorometry, followed by immunocytochemical identification of NPY, phospho-AMPK, and phospho-acetyl-CoA carboxylase (ACC). Ghrelin and AICAR, an AMPK activator, increased [Ca(2+)](i) in neurons isolated from the ARC. The ghrelin-responsive neurons highly overlapped with AICAR-responsive neurons. The neurons that responded to both ghrelin and AICAR were primarily NPY-immunoreactive neurons. Treatment with ghrelin increased phosphorylation of AMPK and ACC. An AMPK inhibitor, compound C, suppressed ghrelin-induced [Ca(2+)](i) increases. These results demonstrate that ghrelin increases [Ca(2+)](i) via AMPK-mediated signaling in the ARC NPY neurons.
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PMID:Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons. 1806 66

The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid beta oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid beta oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent manner.
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PMID:Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. 2033 27

Ghrelin is a circulating brain-gut peptide that is known to exert several metabolic effects such as stimulating appetite, inducing adiposity, increasing bone formation, and influencing the cardiovascular functions. AMP-activated protein kinase (AMPK), a highly conserved heterotrimeric protein that plays a key role in energy homeostasis, has been shown to mediate many of these metabolic effects of ghrelin. Ghrelin is shown to stimulate hypothalamic AMPK activity and inhibit liver and adipose tissue AMPK activity. The effects of ghrelin on AMPK activity can be studied using an elegant kinase assay, which involves immunoprecipitating AMPK protein from the tissue of interest followed by quantifying its enzymatic activity using radiolabeled adenosine triphosphate (ATP) in the presence of a suitable substrate. As a surrogate marker of AMPK activity, AMPK Thr(172) phosphorylation can be measured by Western blotting. Information about the AMPK pathway can also be gained by studying the mRNA expression of various AMPK subunits and by Western blotting for phosphorylated acetyl-CoA carboxylase, a key AMPK target. These methods have been widely used and published for investigating the effects of ghrelin on AMPK activity. In this chapter, we look into these experiments' methodology in detail.
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PMID:Measurement of AMP-activated protein kinase activity and expression in response to ghrelin. 2297 59

Ghrelin is classically known as a central appetite-stimulating hormone but has recently been recognized to have a significant role in peripheral tissue energy metabolism. However, the direct effects of ghrelin on skeletal muscle, a major site for glucose and lipid disposal, remain understudied. We found that the two major ghrelin isoforms, acylated and unacylated ghrelin, were able to significantly increase skeletal muscle fatty acid oxidation (~20%) while incorporation of fatty acids into major lipid pools remained unchanged. The increase in fatty acid oxidation was accompanied by increases in acetyl-CoA carboxylase phosphorylation, a downstream target of AMPK. Ghrelin isoforms had no independent effect on lipolysis under unstimulated conditions, but nearly completely abolished epinephrine-stimulated lipolysis. This effect was generally, but not consistently related to a blunting in the phosphorylation of HSL activation sites, Ser660 and 563. Taken together, these findings suggest that ghrelin isoforms have a direct, acute effect on fatty acid oxidation and lipolysis.
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PMID:Ghrelin stimulates fatty acid oxidation and inhibits lipolysis in isolated muscle from male rats. 3096 94