Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a cellular fuel gauge that regulates metabolic pathways in glucose and fatty acid metabolism and protein synthesis. Recent data strongly implicate the AMPK-acetyl CoA carboxylase (ACC)-malonyl CoA pathway in the hypothalamus in the regulation of food intake, body weight and hepatic glucose production. Furthermore, data indicate that AMPK is a mediator of the effects of adipocyte-derived and gut-derived hormones and peptides on fatty acid oxidation and glucose uptake in peripheral tissues. Studies are now elucidating the potential role of kinases upstream of AMPK in these metabolic effects. In addition, recently, several novel downstream effectors of AMPK have been identified. The AMPK pathway in the hypothalamus and peripheral tissues coordinately integrates inputs from multiple hormones, peptides and nutrients to maintain energy homeostasis.
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PMID:AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. 1670 29

The trillions of microbes that colonize our adult intestines function collectively as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. Given the worldwide epidemic in obesity, there is interest in how interactions between human and microbial metabolomes may affect our energy balance. Here we report that, in contrast to mice with a gut microbiota, germ-free (GF) animals are protected against the obesity that develops after consuming a Western-style, high-fat, sugar-rich diet. Their persistently lean phenotype is associated with increased skeletal muscle and liver levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream targets involved in fatty acid oxidation (acetylCoA carboxylase; carnitine-palmitoyltransferase). Moreover, GF knockout mice lacking fasting-induced adipose factor (Fiaf), a circulating lipoprotein lipase inhibitor whose expression is normally selectively suppressed in the gut epithelium by the microbiota, are not protected from diet-induced obesity. Although GF Fiaf-/- animals exhibit similar levels of phosphorylated AMPK as their wild-type littermates in liver and gastrocnemius muscle, they have reduced expression of genes encoding the peroxisomal proliferator-activated receptor coactivator (Pgc-1alpha) and enzymes involved in fatty acid oxidation. Thus, GF animals are protected from diet-induced obesity by two complementary but independent mechanisms that result in increased fatty acid metabolism: (i) elevated levels of Fiaf, which induces Pgc-1alpha; and (ii) increased AMPK activity. Together, these findings support the notion that the gut microbiota can influence both sides of the energy balance equation, and underscore the importance of considering our metabolome in a supraorganismal context.
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PMID:Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. 1721 Sep 19

Obesity is a major public health problem associated with morbidity and mortality and continues to increase worldwide. This review focuses on the regions of the brain that are important in appetite regulation and the circulating factors implicated in the control of food intake. The hypothalamus is critical in the regulation of food intake containing neural circuits, which produce a number of peptides that influence food intake. The arcuate nucleus of the hypothalamus produces both orexigenic peptides (agouti-related protein and neuropeptide Y) and anorectic peptides (alpha-melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript). The lateral hypothalamus produces the orexigenic peptides (melanin-concentrating hormone and orexins). Other hypothalamic factors recently implicated in appetite regulation include the endocannabinoids, brain-derived neurotrophic factor, nesfatin-1, AMP-activated protein kinase, mammalian target of rapamycin protein, and protein tyrosine phosphatase. Circulating factors that affect food intake mediate their effects by signaling to the hypothalamus and/or brainstem. A number of circulating factors are produced by peripheral organs, for example, leptin by adipose tissue, insulin and pancreatic polypeptide by the pancreas, gut hormones (e.g., ghrelin, obestatin, glucagon-like peptide-1, oxyntomodulin, peptide YY), and triiodothyronine by the thyroid gland. Circulating carbohydrates, lipids, and amino acids also affect appetite regulation. Knowledge regarding appetite regulation has vastly expanded in recent years providing targets for antiobesity drug design.
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PMID:Appetite regulation: an overview. 1754 73

The gut hormone ghrelin is known to activate hypothalamic AMPK, a crucial metabolic sensor controlling energy balance. In this issue of Cell Metabolism, Anderson et al. (2008) show that CaMKK2 mediates this effect by forming a unique complex of AMPKalpha/beta with acetyl-CoA carboxylase (ACC) in a pathway distinct from the more established AMP/LKB1 pathway.
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PMID:The CAMplexities of central ghrelin. 1846 Mar 29

The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.
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PMID:UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. 1866 43

The complex control of food intake and energy metabolism in mammals relies on the ability of the brain to integrate multiple signals indicating the nutritional state and the energy level of the organism and to produce appropriate responses in terms of food intake, energy expenditure, and metabolic activity. Central regulation of feeding is organized as a long-loop mechanism involving humoral signals and afferent neuronal pathways to the brain, processing in hypothalamic neuronal circuits, and descending commands using vagal and spinal neurons. Sensor mechanisms or receptors sensitive to glucose and fatty acid metabolism, neuropeptide and cannabinoid receptors, as well as neurotransmitters and neuromodulators synthesized and secreted within the brain itself are all signals integrated in the hypothalamus, which therefore functions as an integrator of signals from central and peripheral structures. Homeostatic feedback mechanisms involving afferent neuroendocrine inputs from peripheral organs, like adipose tissue, gut, stomach, endocrine pancreas, adrenal, muscle, and liver, to hypothalamic sites thus contribute to the maintenance of normal feeding behavior and energy balance. In addition to transcriptional events, peripheral hormones may also alter firing and/or connection (synaptology) of hypothalamic neuronal networks in order to modulate food intake. Moreover, intracellular energy sensing and subsequent biochemical adaptations, including an increase in AMP-activated protein kinase activity, occur in hypothalamic neurons. Understanding the regulation of appetite is clearly a major research effort but also seems promising for the development of novel therapeutic strategies for obesity.
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PMID:Feeding behavior in mammals including humans. 1945 43

Dietary protein and amino acids, including glutamate, generate signals involved in the control of gastric and intestinal motility, pancreatic secretion, and food intake. They include postprandial meal-induced visceral and metabolic signals and associated nutrients (eg, amino acids and glucose), gut neuropeptides, and hormonal signals. Protein reduces gastric motility and stimulates pancreatic secretions. Protein and amino acids are also more potent than carbohydrate and fat in inducing short-term satiety in animals and humans. High-protein diets lead to activation of the noradrenergic-adrenergic neuronal pathway in the brainstem nucleus of the solitary tract and in melanocortin neurons of the hypothalamic arcuate nucleus. Moreover, some evidence indicates that circulating concentrations of certain amino acids could influence food intake. Leucine modulates the activity of energy and nutrient sensor pathways controlled by AMP-activated protein kinase and mammalian target of rapamycin in the hypothalamus. At the brain level, 2 afferent pathways are involved in protein and amino acid monitoring: the indirect neural (mainly vagus-mediated) and the direct humoral pathways. The neural pathways transfer preabsorptive and visceral information through the vagus nerve that innervates part of the orosensory zone (stomach, duodenum, and liver). Localized in the brainstem, the nucleus of the solitary tract is the main projection site of the vagus nerve and integrates sensory information of oropharyngeal, intestinal, and visceral origins. Ingestion of protein also activates satiety pathways in the arcuate nucleus, which is characterized by an up-regulation of the melanocortin pathway (alpha-melanocyte-stimulating, hormone-containing neurons) and a down-regulation of the neuropeptide Y pathway.
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PMID:Protein, amino acids, vagus nerve signaling, and the brain. 1964 Sep 48

Glucagon-like peptide (GLP)-1 is a potent glucose-dependent insulinotropic gut hormone released from intestinal L cells. Our previous studies showed that berberine increased GLP-1 secretion in streptozotocin-induced diabetic rats. The aim of this study was to investigate whether berberine affected GLP-1 release in normal rats and in NCI-H716 cells. Proglucagon and prohormone convertase 3 genes regulating GLP-1 biosynthesis were analyzed by RT-PCR. Effects of pharmacological inhibitors on berberine-mediated GLP-1 release were studied. In vivo, 5-week treatment of berberine enhanced GLP-1 secretion induced by glucose load and promoted proglucagon mRNA expression as well as L cell proliferation in intestine. In vitro, berberine concentration-dependently stimulated GLP-1 release in NCI-H716 cells. Berberine also promoted both prohormone convertase 3 and proglucagon mRNA expression. Chelerythrine (inhibitor of PKC) concentration-dependently suppressed berberine-mediated GLP-1 secretion. Compound C (inhibitor of AMPK) also inhibited berberine-mediated GLP-1 secretion. But only low concentrations of H89 (inhibitor of PKA) showed inhibitory effects on berberine-mediated GLP-1 release. The present results demonstrated that berberine showed its modulation on GLP-1 via promoting GLP-1 secretion and GLP-1 biosynthesis. Some signal pathways including PKC-dependent pathway were involved in this process. Elucidation of mechanisms controlling berberine-mediated GLP-1 secretion may facilitate the understanding of berberine's antidiabetic effects.
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PMID:Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. 1994 41

The larval phase of the Drosophila life cycle is characterized by constant food intake, resulting in a two hundred-fold increase in mass over four days. Here we show that the conserved energy sensor AMPK is essential for nutrient intake in Drosophila. Mutants lacking dAMPKalpha are small, with low triglyceride levels, small fat body cells and early pupal lethality. Using mosaic analysis, we find that dAMPKalpha functions as a nonautonomous regulator of cell growth. Nutrient absorption is impaired in dAMPKalpha mutants, and this defect stems not from altered gut epithelial cell polarity but from impaired peristaltic activity. Expression of a wild-type dAMPKalpha transgene or an activated version of the AMPK target myosin regulatory light chain (MRLC) in the dAMPKalpha mutant visceral musculature restores gut function and growth. These data suggest strongly that AMPK regulates visceral smooth muscle function through phosphorylation of MRLC. Furthermore, our data show that in Drosophila, AMPK performs an essential cell-nonautonomous function, serving the needs of the organism by promoting activity of the visceral musculature and, consequently, nutrient intake.
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PMID:AMPK supports growth in Drosophila by regulating muscle activity and nutrient uptake in the gut. 2047 98

Ghrelin is a circulating growth-hormone-releasing and appetite-inducing brain-gut peptide. It is a known natural ligand of the growth hormone secretagogue receptor (GHS-R). Ghrelin is acylated on its serine 3 residue by ghrelin O-acyltransferase (GOAT). The acylation is essential for its orexigenic and adipogenic effects. Ghrelin exerts its central orexigenic effect through activation of various hypothalamic and brain stem neurons. Several new intracellular targets/mediators of the appetite-inducing effect of ghrelin in the hypothalamus have recently been identified, including the AMP-activated protein kinase, its upstream kinase calmodulin kinase kinase 2, components of the fatty acid pathway and the uncoupling protein 2. The ghrelin/GOAT/GHS-R system is now recognised as a potential target for the development of anti-obesity treatment. Ghrelin regulates the function of the anterior pituitary through stimulation of secretion not only of growth hormone, but also of adrenocorticotrophin and prolactin. The implication of ghrelin and its receptor in the pathogenesis of the neuroendocrine tumors will also be discussed in this review.
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PMID:Ghrelin's role as a major regulator of appetite and its other functions in neuroendocrinology. 2054 66


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