AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Claret, Marc; Smith, Mark A.; Batterham, Rachel L.; Selman, Colin; Choudhury, Agharul I.; Fryer, Lee G.D.; Clements, Melanie; Al-Qassab, Hind; Heffron, Helen; Xu, Allison; Speakman, John R.; Barsh, Gregory S.; Viollet, Benoı̂t; Vaulont, Sophie; Ashford, M. L. J.; Carling, David; Withers, Dominic J.

doi:10.1172/jci31516

Cited by 448 publications

(505 citation statements)

References 56 publications

(113 reference statements)

Supporting

Mentioning

462

Contrasting

Unclassified

Order By: Relevance

“…However, the electrophysiological responses of the neurones to insulin were preserved. While these results do not support models that propose that AMPK is a key central regulator of food intake in the hypothalamus, interesting additional findings were that neither POMC nor AgRP neurones from the knockouts hyperpolarized in response to low glucose, unlike equivalent neurones from wild type mice [31]. This suggests that, although AMPK may not be directly involved in the response of the hypothalamus to hormones like leptin and insulin, it may be involved in the response to hypoglycaemia.…”

Section: Ampk -Regulation By Adipokinescontrasting

confidence: 82%

“…A problem with the studies that have measured AMPK activity in the hypothalamus is that even very small regions dissected from it contain many different types of neurone that might be responding to the various stimuli in a heterogeneous manner. In an attempt to overcome this problem, the a2 isoform of AMPK has been specifically knocked out using the Cre-loxP system in POMC-and AgRP-expressing neurones of mice [31]. Knocking out a2 in these neurones might have been expected to mimic the effects of leptin to generate a lean phenotype.…”

Section: Ampk -Regulation By Adipokinesmentioning

confidence: 99%

See 1 more Smart Citation

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

2007

View full text Add to dashboard Cite

Obesity, type 2 diabetes and the metabolic syndrome are disorders of energy balance, which the AMP-activated protein kinase (AMPK) regulates both at the cellular and whole body levels. AMPK switches cells from an anabolic state where nutrients are taken up and stored, to a catabolic state where they are oxidized. Drugs that activate AMPK indirectly (metformin and thiazolidinediones) are now the mainstay of treatment for type 2 diabetes, but more direct AMPK activators may have fewer side effects. However, activating mutations in AMPK can cause heart disease, and it will be important to look for adverse effects in the heart.

show abstract

Section: Ampk -Regulation By Adipokinescontrasting

confidence: 82%

Section: Ampk -Regulation By Adipokinesmentioning

confidence: 99%

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

2007

View full text Add to dashboard Cite

show abstract

“…The more wellknown role of leptin is to repress appetite (and hence energy intake) via effects on the hypothalamus, and Kahn and co-workers have suggested that this is mediated by inhibition of AMPK (29) . Results with knock-out mice that lack AMPK in hypothalamic neurones have not fully supported this model, but do support the idea that AMPK is involved in glucose sensing in the hypothalamus (19) .…”

Section: Regulation Of Amp-activated Protein Kinase By Adipokines Andmentioning

confidence: 87%

“…GLUT2 and glucokinase, and fluctuations in glucose within the normal physiological range alter the rate of glucose metabolism and consequently modulate the AMPK activity. In these cells, the activation of AMPK appears to play important roles in the physiological responses to hypoglycaemia, such as reduced secretion of insulin and increased secretion of glucagon and adrenaline by the pancreas and adrenal medulla (17)(18)(19)(20) . Deprivation of oxygen (hypoxia) is another stress that can limit catabolism, thus causing increases in AMP: ATP and AMPK activation.…”

Section: Activation Of Mammalian Amp-activated Protein Kinase By Metamentioning

confidence: 99%

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Hardie

2010

Proc. Nutr. Soc.

115

View full text Add to dashboard Cite

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP :ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-ofrapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished. Muscle: Exercise: Type 2 diabetes: NutraceuticalsAnimal cells take up fuel molecules such as glucose or fatty acids, and oxidise them to CO 2 via the process of catabolism. Much of the energy released during this process is used to convert ADP to ATP, which can be likened to the chemicals in a rechargeable battery. Extending this analogy, catabolism charges up the battery by converting ADP to ATP, whereas most other cellular activities (e.g. growth, division, secretion and movement) require energy and are driven by the conversion of ATP back to ADP, thus draining the battery. Just as machines that utilise rechargeable batteries (such as laptop computers or electric cars) require systems to monitor the state of the battery, cells require systems to monitor their ATP : ADP ratio and match the rates of uptake and consumption of carbon nutrients to the rate of ATP utilisation. The topic of this review is the AMP-activated protein kinase (AMPK), which is the major system responsible for achieving this task in eukaryotes. Researchers who wish to understand disorders of energy balance, such as obesity and type-2 diabetes, have been particularly interested in the system. Protein kinases, including AMPK, are signalling enzymes that modify the function of target proteins by transferring phosphate groups from ATP to side chains of specific amino acids, usually serine o...

show abstract

“…90 Inactivation of this kinase either in POMC or in NPY/Agrp neurons suppressed the regulation by glucose of their firing activity. 91 However, absence of this enzyme from the POMC neurons led to increased feeding and body weight. As POMC neurons are anorexigenic, AMP kinase, which is activated by low glucose, should be expected to suppress POMC expression to increase feeding.…”

Section: Feeding Controlmentioning

confidence: 99%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

View full text Add to dashboard Cite

The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

show abstract

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Cited by 448 publications

References 56 publications

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Contact Info

Product

Resources

About