AMPK(AMP-activated Protein Kinase) an intracellular energy sensor maintaining the energy balance.AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY(3-36) (PYY) and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity, and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide (AICA) riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.

 

Human gene mutations affecting cardiac energetics and metabolism. Energy substrate utilization is directed by critical metabolic sensors in myocytes, including AMP-activated protein kinase (AMPK), which, in response to increased AMP/ATP levels, phosphorylates target proteins and thereby regulates glycogen and fatty acid metabolism, critical energy sources for the heart. Glycogen metabolism involves a large number of proteins including -galactosidase A (mutated in Fabry disease) and LAMP2 (mutated in Danon disease). Glycogen and fatty acids are substrates for multiprotein complexes located within the mitochondria for the synthesis of ATP. KATP channels composed of an enzyme complex and a potassium pore participate in decoding metabolic signals to maximize cellular functions during stress adaptation. Human mutations (orange text) that cause cardiomyopathies have been identified in the regulatory SUR2A subunit of KATP, the 2 subunit of AMPK, mitochondrial proteins, -galactosidase A, and LAMP2.

Morita H., et al. J. Clin. Invest. 115:518-526 (2005). doi:10.1172/JCI200524351.

 

 

Role of AMPK in regulating energy balance at the whole-body level. Green arrows indicate positive effects, and red lines with bars indicate negative effects. In the hypothalamus, activation of AMPK in response to low glucose or leptin levels increases food intake (18, 19); references for other effects of AMPK activation can be found in recent reviews (1). FA, fatty acid.

Role of AMPK in regulating energy balance at the single-cell level. The way in which the AMPK system controls the balance between ATP consumption (e.g., by biosynthesis, cell growth, or muscle contraction) and ATP production via catabolism is illustrated. If the rate of ATP consumption exceeds its rate of production, ADP will tend to rise and be converted to AMP by the enzyme adenylate kinase. The rise in level of the activating ligand AMP, coupled with the fall in level of the inhibitory nucleotide ATP, activates AMPK, which then switches off ATP-consuming processes and switches on catabolism in an attempt to redress the balance.

D. Grahame Hardie. J. Clin. Invest. 114:465-468 (2004). doi:10.1172/JCI200422683.

 

Proposed model for role of AMPK in anorexigenic signalling in the hypothalamus. Anorexigenic signals activate POMC neurons in ARH (arcuate hypothalamus) via STAT3 and possibly also PI3 kinase, generating a second anorexigenic signal mediated by -melanocyte stimulating hormone (-MSH). In contrast, the anorexigenic signals suppress the activity of NPY/AGRP neurons, partly via STAT3 and possibly also PI3 kinase, and decrease AMPK activity in these neurons. Decreased AMPK activity enhances the suppression of NPY/AGRP effects, leading to activation of MC4 receptor signalling in PVH (paraventricular hypothalamus) neurons. MC4 receptor activation decreases AMPK activity in PVH, which probably further enhances neurotransmission required for regulation of food intake and energy balance. Decreased NPY signalling in PVH functionally enhances the MC4 receptor signalling pathway. In addition, decreased AMPK activity in other hypothalamic regions may enhance the MC4 receptor signalling pathway by projections to the ARH or PVH (for example, NPY neurons in DMH) and recruit additional pathways that may regulate food intake.

MINOKOSHI Y., et al. Nature, 428, 569 - 574 (01 April 2004); doi:10.1038/nature02440

 

Leptin's control of fat in skeletal muscle2. In cells, there is a balance between transport of fatty acids into mitochondria and their subsequent oxidation, and storage of these compounds as triglycerides in the cytoplasm. This balance is regulated mainly by malonyl CoA, a fatty acid that is generated by the enzyme acetyl CoA carboxylase (ACC). Malonyl CoA inhibits transport of fatty acids into mitochondria, thereby preventing their oxidation12. Leptin causes the phosphorylation of AMP-activated protein kinase (AMPK), which in turn phosphorylates ACC, inactivating it13. Leptin thus inhibits malonyl CoA synthesis, leading to greater mitochondrial import and consumption of fatty acids. These events seem to result both from the direct action of leptin on skeletal muscle and from its indirect influence that operates through the hypothalamus.

Friedman J. Nature. 2002 Jan 17;415(6869):268-9

Figure 2 Model for the involvement of AMPK in the regulation of skeletal muscle glucose transport in response to AICAR, hypoxia, electrical stimulation and exercise. It is proposed that AICAR- and hypoxia-induced glucose uptake in skeletal muscle are AMPK-dependent, whereas exercise-induced glucose uptake is not or is only partially dependent on AMPK. It should be considered that during electrically stimulated muscle contraction (and perhaps exercise) a part of the stimulus to glucose transport may be due to hypoxia involving AMPK. Arrow thickness reflects the proposed relative involvement of the different pathways.

Nielsen JN, et al. Biochem Soc Trans. 2003 Feb;31(Pt 1):186-90

Malonyl-CoA content of muscle is controlled by the relative rate of synthesis by acetyl-CoA carboxylase (ACC) and the rate of degradation by malonyl-CoA decarboxylase (MCD). AMPK phosphorylates (P) and inactivates ACC. On the basis of effects of 5-aminoimidazole- 4-carboxamide -riboside (AICAR) on activation of MCD in incubated extensor digitorum longus, AMPK is hypothesized to phosphorylate and activate MCD (Ref. 80). These changes could result in a decline in malonyl-CoA (rat muscle studies). Winder WW. J Appl Physiol. 2001 Sep;91(3):1017-28

C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase

Energy homeostasis and feeding are regulated by the central nervous system (CNS). C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel CNS pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating C75’s anorexic effects. AICAR, an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK a subunit (pAMPKα) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKa levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKα levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKα and phosphorylated cAMP response element binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus.

J. Biol. Chem, 10.1074/jbc.M402165200

 

AMP-activated protein kinase plays a role in the control of food intake

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY(3-36) (PYY) and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity, and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide (AICA) riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.

Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ. J Biol Chem. 2004 Jan 23 [Epub ahead of print]

 

Multiple effects of AMPK on liver, adipose tissue, muscle metabolism, and pancreatic islets

 

Postulated mechanisms of increase in fatty acid oxidation and on glucose uptake in skeletal muscle in response to contraction. AMPKK, AMP-activated protein kinase kinase; [5'-AMP] and [CP], 5'-AMP and creatine phosphate concentrations, respectively; AMPK-OH and AMPK-OP, nonphosphorylated and phosphorylated AMPK, respectively; ACC, acetyl-CoA carboxylase; FFA, free fatty acids.

 

Two mechanisms for stimulation of glucose uptake in skeletal muscle, one mediated by insulin and one triggered by muscle contraction. The hypothesis of mediation of the contraction effect by AMPK is based on the observations that exercise and electrical stimulation increase AMPK activity and glucose uptake and that glucose uptake is increased by chemical activation of AMPK with AICA-riboside. IR, insulin receptor; IRS-1, insulin receptor substrate 1; PI 3-kinase, phosphatidylinositol 3-kinase.

Winder WW, Hardie DG. Am J Physiol. 1999 Jul;277(1 Pt 1):E1-10

 

 

The AMP-activated protein kinase cascade--a unifying system for energy control

Carling D. Trends Biochem Sci. 2004 Jan;29(1):18-24

Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion

Leclerc I, et al. Am J Physiol Endocrinol Metab. 2004 Feb 10 [Epub ahead of print]

 

 

A model for C75-induced changes in energy flux that alter AMPK activity to modulate CREB-NPY pathway signaling in the arcuate nucleus.

Kim EK et al. JBC Papers in Press. Published on March 17, 2004 as Manuscript M402165200. 

Short-term signals regulating food intake. Signals from the GI tract and the liver are involved in short-term regulation of feeding. Afferent signals travel in vagal nerve fibers from stretch receptors, and chemoreceptors activated by the presence of nutrients in the stomach and proximal small intestine are involved in meal termination. Nutrients arriving via the portal vein may also trigger vagal afferent signals from the liver. Glucose can modulate food intake by acting on glucose-responsive neurons in the CNS. Ketones appear to decrease appetite. In response to nutrient stimulation, the proximal intestine releases cholecystokinin (CCK), which reaches the liver via the portal vein and the CNS via the systemic circulation; CCK may act on CCK-A receptors at both sites to inhibit food intake. Endocrine L cells in the terminal small intestine (ileum) release glucagon-like peptide-1 (GLP-1), which inhibits feeding, most likely at a hepatic site or by inhibiting gastric emptying. The short-term signals by themselves do not produce sustained alterations in energy intake and body adiposity.

Long-term signals regulating food intake and energy homeostasis. Insulin and leptin are the two most important long-term regulators of food intake and energy balance. Both insulin and leptin act in the CNS to inhibit food intake and to increase energy expenditure, most likely by activating the sympathetic nervous system (SNS). Insulin is secreted from ?cells in the endocrine pancreas in response to circulating nutrients (glucose and amino acids) and to the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, which are released during meal ingestion and absorption. Insulin can also act indirectly by stimulating leptin production from adipose tissue via increased glucose metabolism. In contrast, dietary fat and fructose do not stimulate insulin secretion and therefore do not increase leptin production. There is also evidence that leptin can inhibit insulin secretion from the pancreas. The gastric hormone ghrelin increases food intake and decreases fat oxidation in rodents and may have an anabolic role in long-term food intake regulation. The long-term signals interact with the short-term signals in the regulation of energy homeostasis and appear to set sensitivity to the satiety-producing effects of short-term signal such as CCK. Havel PJ.  Exp Biol Med (Maywood). 2001 Dec;226(11):963-77