154 results found
Carling D, 2019, AMPK hierarchy: A matter of space and time, Cell Research, ISSN: 1001-0602
AMP-activated protein kinase (AMPK) is a key sensor of energy balance in eukaryotic cells, responding to low energy status by switching off anabolic pathways and upregulating catabolic processes. Zong and colleagues now show that different intensities of stimulation trigger activation of specific subcellular pools of AMPK, resulting in phosphorylation of different downstream targets.
Steinberg GR, Carling D, 2019, AMP-activated protein kinase: the current landscape for drug development, Nature Reviews Drug Discovery, ISSN: 1474-1776
Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elicit beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established.
Pollard AE, Martins L, Muckett PJ, et al., 2019, AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue, Nature Metabolism, Vol: 1, Pages: 340-349, ISSN: 2522-5812
Obesity results from a chronic imbalance between energy intake and energy output but remains difficult to prevent or treat in humans. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an important regulator of energy homeostasis1,2,3 and is a molecular target of drugs used for the treatment of metabolic diseases, including obesity4,5. Here we show that mice expressing a gain-of-function AMPK mutant6 display a change in morphology of subcutaneous white adipocytes that is reminiscent of browning. However, despite a dramatic increase in mitochondrial content, Ucp1 expression is undetectable in these adipocytes. In response to a high-fat diet (HFD), expression of skeletal muscle–associated genes is induced in subcutaneous white adipocytes from the gain-of-function AMPK mutant mice. Chronic genetic AMPK activation results in protection against diet-induced obesity due to an increase in whole-body energy expenditure, most probably because of a substantial increase in the oxygen consumption rate of white adipose tissue. These results suggest that AMPK activation enriches, or leads to the emergence of, a population of subcutaneous white adipocytes that produce heat via Ucp1-independent uncoupling of adenosine triphosphate (ATP) production on a HFD. Our findings indicate that AMPK activation specifically in adipose tissue may have therapeutic potential for the treatment of obesity.
Penfold L, Woods A, Muckett P, et al., 2018, CAMKK2 promotes prostate cancer independently of AMPK via increased lipogenesis, Cancer Research, Vol: 78, Pages: 6747-6761, ISSN: 1538-7445
New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) β1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer.
Hinchy EC, Gruszczyk AV, Willows R, et al., 2018, Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 293, Pages: 17208-17217, ISSN: 0021-9258
Mitochondrial reactive oxygen species (ROS) production is a tightly regulated redox signal that transmits information from the organelle to the cell. Other mitochondrial signals, such as ATP, are sensed by enzymes, including the key metabolic sensor and regulator, AMP-activated protein kinase (AMPK). AMPK responds to the cellular ATP/AMP and ATP/ADP ratios by matching mitochondrial ATP production to demand. Previous reports proposed that AMPK activity also responds to ROS, by ROS acting on redox-sensitive cysteine residues (Cys-299/Cys-304) on the AMPK α subunit. This suggests an appealing model in which mitochondria fine-tune AMPK activity by both adenine nucleotide–dependent mechanisms and by redox signals. Here we assessed whether physiological levels of ROS directly alter AMPK activity. To this end we added exogenous hydrogen peroxide (H2O2) to cells and utilized the mitochondria-targeted redox cycler MitoParaquat to generate ROS within mitochondria without disrupting oxidative phosphorylation. Mitochondrial and cytosolic thiol oxidation was assessed by measuring peroxiredoxin dimerization and by redox-sensitive fluorescent proteins. Replacing the putative redox-active cysteine residues on AMPK α1 with alanines did not alter the response of AMPK to H2O2. In parallel with measurements of AMPK activity, we measured the cell ATP/ADP ratio. This allowed us to separate the effects on AMPK activity due to ROS production from those caused by changes in this ratio. We conclude that AMPK activity in response to redox changes is not due to direct action on AMPK itself, but is a secondary consequence of redox effects on other processes, such as mitochondrial ATP production.
Thomas EC, Hook SC, Gray A, et al., 2018, Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity, Biochemical Journal, Vol: 475, Pages: 2969-2983, ISSN: 1470-8728
AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energyhomeostasis which achieves this through the phosphorylation of a myriad of downstreamtargets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucoseuptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which maybe important in regulating glucose uptake. Here, we show AMPK heterotrimers containingthe α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosinebinding (PTB) domains of TBC1D1 and is increased by two different pharmacologicalactivators of AMPK (AICAR and A769962). The interaction enhances the efficiency bywhich AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237. Furthermore, theinteraction is reduced by a naturally occurring R125W mutation in the PTB1 domain ofTBC1D1, previously found to be associated with severe familial obesity in females, with aconcomitant reduction in Ser237 phosphorylation. Our observations provide evidence fora functional difference between AMPK α-subunits and extend the repertoire of proteinkinases that interact with substrates via stabilisation mechanisms that modify the efficacyof substrate phosphorylation.
AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca(2+) release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.
Willows R, Sanders MJ, Xiao B, et al., 2017, Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells, Biochemical Journal, Vol: 474, Pages: 3059-3073, ISSN: 1470-8728
AMP-activated protein kinase (AMPK) plays a major role in regulating metabolism andhas attracted significant attention as a therapeutic target for treating metabolic disorders.AMPK activity is stimulated more than 100-fold by phosphorylation of threonine 172(Thr172). Binding of AMP to the γ subunit allosterically activates the kinase. Additionally,many small molecules, e.g. 991, have been identified that bind between the kinasedomain and the carbohydrate-binding module of the β subunit, stabilising their interactionand leading to activation. It was reported recently that non-phosphorylated Thr172 AMPKis activated by AMP and A769662. We present here the crystal structure of non-phosphorylatedThr172 AMPK in complex with AMP and 991. This structure reveals that theactivation loop, as well as the complex overall, is similar to the Thr172 phosphorylatedcomplex. We find that in the presence of AMP and 991 non-phosphorylated Thr172,AMPK is much less active than the Thr172 phosphorylated enzyme. In human cells, thebasal level of Thr172 phosphorylation is very low (∼1%), but is increased 10-fold by treatmentwith 2-deoxyglucose. In cells lacking the major Thr172 kinases, LKB1 and CaMKKβ,Thr172 phosphorylation is almost completely abolished, and AMPK activity is virtuallyundetectable. Our data show that AMP and 991 binding to non-phosphorylated Thr172AMPK can induce an ordered, active-like, conformation of the activation loop explaininghow AMPK activity can be measured in vitro without Thr172 phosphorylation. However, ina cellular context, phosphorylation of Thr172 is critical for significant activation of AMPK.
Willows R, Navaratnam N, Lima A, et al., 2017, Effect of different γ subunit isoforms on the regulation of AMPK, Biochemical Journal, Vol: 474, Pages: 1741-1754, ISSN: 1470-8728
AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. AMPK activation results in a wide range of downstream responses, many of which are associated with improved metabolic outcome, making AMPK an attractive target for the treatment of metabolic diseases. AMPK is a heterotrimeric complex consisting of a catalytic subunit (α) and two regulatory subunits (β and γ). The γ-subunit harbours the nucleotide-binding sites and plays an important role in AMPK regulation in response to cellular energy levels. In mammals, there are three isoforms of the γ-subunit and these respond differently to regulation by nucleotides, but there is limited information regarding their role in activation by small molecules. Here, we determined the effect of different γ-isoforms on AMPK by a direct activator, 991. In cells, 991 led to a greater activation of γ2-containing AMPK complexes compared with either γ1 or γ3. This effect was dependent on the long N-terminal region of the γ2-isoform. We were able to rule out an effect of Ser108 phosphorylation, since mutation of Ser108 to alanine in the β2-isoform had no effect on activation of AMPK by 991 in either γ1- or γ2-complexes. The rate of dephosphorylation of Thr172 was slower for γ2- compared with γ1-complexes, both in the absence and presence of 991. Our studies show that activation of AMPK by 991 depends on the nature of the γ-isoform. This finding may have implications for the design of isoform-selective AMPK activators.
Carling D, Woods A, Williams JR, et al., 2017, Liver-specific activation of AMPK prevents steatosis on a high fructose diet, Cell Reports, Vol: 18, Pages: 3043-3051, ISSN: 2211-1247
AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the γ1 subunit (γ1D316A) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma).
Carling D, 2017, AMPK signalling in health and disease, Current Opinion in Cell Biology, Vol: 45, Pages: 31-37, ISSN: 1879-0410
In eukaryotic cells AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance. AMPK responds to changes in intracellular adenine nucleotide levels, being activated by an increase in AMP/ADP relative to ATP. Activation of AMPK increases the rate of catabolic (ATP-generating) pathways and decreases the rate of anabolic (ATP-utilising) pathways. In addition to its role in maintaining intracellular energy balance, AMPK regulates whole body energy metabolism. Given its key role in controlling energy homeostasis, AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases, including type 2 diabetes and, more recently, cancer. Here I review the regulation of AMPK and its potential as a target for therapeutic intervention in human disease.
Boyle JJ, Seneviratne AA, Haskard DO, et al., 2017, Oral Metformin Profoundly Suppresses Atherosclerotic Lesion Development In Vivo Independently of Glucose Lowering in a Mild Hyperlipidemic Model Via AMPK, 2nd Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 8-9, ISSN: 1018-1172
Maioli V, Chennell G, Sparks H, et al., 2016, Time-lapse 3-D measurements of a glucose biosensor in multicellular spheroids by light sheet fluorescence microscopy in commercial 96-well plates, Scientific Reports, Vol: 6, ISSN: 2045-2322
Light sheet fluorescence microscopy has previously been demonstrated on a commercially available inverted fluorescence microscope frame using the method of oblique plane microscopy (OPM). In this paper, OPM is adapted to allow time-lapse 3-D imaging of 3-D biological cultures in commercially available glass-bottomed 96-well plates using a stage-scanning OPM approach (ssOPM). Time-lapse 3-D imaging of multicellular spheroids expressing a glucose Förster resonance energy transfer (FRET) biosensor is demonstrated in 16 fields of view with image acquisition at 10 minute intervals. As a proof-of-principle, the ssOPM system is also used to acquire a dose response curve with the concentration of glucose in the culture medium being varied across 42 wells of a 96-well plate with the whole acquisition taking 9 min. The 3-D image data enable the FRET ratio to be measured as a function of distance from the surface of the spheroid. Overall, the results demonstrate the capability of the OPM system to measure spatio-temporal changes in FRET ratio in 3-D in multicellular spheroids over time in a multi-well plate format.
Chennell G, Willows RJW, Warren SC, et al., 2016, Imaging of Metabolic Status in 3D Cultures with an Improved AMPK FRET Biosensor for FLIM, Sensors, Vol: 16, ISSN: 1424-8239
We describe an approach to non-invasively map spatiotemporal biochemical and physiological changes in 3D cell culture using Forster Resonance Energy Transfer (FRET) biosensors expressed in tumour spheroids. In particular, we present an improved Adenosine Monophosphate (AMP) Activated Protein Kinase (AMPK) FRET biosensor, mTurquoise2 AMPK Activity Reporter (T2AMPKAR), for fluorescence lifetime imaging (FLIM) readouts that we have evaluated in 2D and 3D cultures. Our results in 2D cell culture indicate that replacing the FRET donor, enhanced Cyan Fluorescent Protein (ECFP), in the original FRET biosensor, AMPK activity reporter (AMPKAR), with mTurquoise2 (mTq2FP), increases the dynamic range of the response to activation of AMPK, as demonstrated using the direct AMPK activator, 991. We demonstrated 3D FLIM of this T2AMPKAR FRET biosensor expressed in tumour spheroids using two-photon excitation.
Siggs OM, Stockenhuber A, Deobagkar-Lele M, et al., 2016, Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: E3706-E3715, ISSN: 1091-6490
Folliculin (FLCN) is a tumor-suppressor protein mutated in the Birt–Hogg–Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive loss-of-function variant of Fnip1. Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells. FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK. Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium, whereas AMPK-dependent unc-51–like autophagy activating kinase 1 (ULK1) phosphorylation and autophagy were increased in FNIP1-deficient B-cell progenitors. These data support a role for FNIP1 as a negative regulator of AMPK.
Trousil S, Kaliszczak M, Schug Z, et al., 2016, The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth., Oncotarget, Vol: 7, Pages: 37103-37120, ISSN: 1949-2553
The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2-2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids.
Maioli V, Gorlitz F, Warren S, et al., 2016, Three-dimensional fluorescence imaging by stage-scanning oblique plane microscopy, Conference on Three-Dimensional and Multidimensional Microscopy - Image Acquisition and Processing XXIII, Publisher: SPIE, ISSN: 0277-786X
Yavari A, Stocker CJ, Ghaffari S, et al., 2016, Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function., Cell Metabolism, Vol: 23, Pages: 821-836, ISSN: 1932-7420
Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.
Johanns M, Lai Y-C, Hsu M-F, et al., 2016, AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B, Nature Communications, Vol: 7, ISSN: 2041-1723
Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the Vmax of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation.
Seneviratne A, Carling D, Haskard DO, et al., 2016, Oral metformin profoundly suppresses atherosclerotic lesion development in vivo independently of glucose-lowering in a mild hyperlipidemic model, Atherosclerosis, Vol: 244, Pages: E2-E2, ISSN: 1879-1484
Smith MA, Katsouri L, Irvine EE, et al., 2015, Ribosomal S6K1 in POMC and AgRP neurons regulates glucose homeostasis but not feeding behavior in mice, Cell Reports, Vol: 11, Pages: 335-343, ISSN: 2211-1247
Rousset CI, Leiper FC, Kichev A, et al., 2015, A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice, JOURNAL OF NEUROCHEMISTRY, Vol: 133, Pages: 242-252, ISSN: 0022-3042
Hussain S, Richardson E, Ma Y, et al., 2014, Glucokinase activity in the arcuate nucleus regulates glucose intake, Journal of Clinical Investigation, Vol: 125, ISSN: 1558-8238
Ye T, Bendrioua L, Carmena D, et al., 2014, The mammalian AMP-activated protein kinase complex mediates glucose regulation of gene expression in the yeast Saccharomyces cerevisiae, FEBS LETTERS, Vol: 588, Pages: 2070-2077, ISSN: 0014-5793
Frost G, Sleeth ML, Sahuri-Arisoylu M, et al., 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nature Communications, Vol: 5, ISSN: 2041-1723
Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo11C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13C high-resolution magic-angle-spinning that 13C acetate from fermentation of 13C-labelled carbohydrate in the colon increases hypothalamic 13C acetate above baseline levels. Hypothalamic 13C acetate regionally increases the 13C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation.
Wan X, Huo Y, Johns M, et al., 2014, HEME AND METFORMIN COORDINATE HUMAN AND MURINE MACROPHAGE HEME OXYGENASE 1 EXPRESSION WITH FOAM CELL RESISTANCE PARTLY VIA ADENOSINE MONOPHOSPHATE KINASE AND ACTIVATING TRANSCRIPTION FACTOR 1 (AMPK-ATF1), Autumn Meeting of the British-Atherosclerosis-Society (BAS), Publisher: ELSEVIER IRELAND LTD, Pages: E4-E4, ISSN: 0021-9150
Xiao B, Sanders MJ, Carmena D, et al., 2013, Structural basis of AMPK regulation by small molecule activators, NATURE COMMUNICATIONS, Vol: 4, ISSN: 2041-1723
Wan X, Huo Y, Johns M, et al., 2013, 5 '-AMP-Activated Protein Kinase-Activating Transcription Factor 1 Cascade Modulates Human Monocyte-Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 33, Pages: 2470-2480, ISSN: 1079-5642
Lallet-Daher H, Wiel C, Gitenay D, et al., 2013, Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation, CANCER RESEARCH, Vol: 73, Pages: 5253-5265, ISSN: 0008-5472
Ruderman NB, Carling D, Prentki M, et al., 2013, AMPK, insulin resistance, and the metabolic syndrome, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 2764-2772, ISSN: 0021-9738
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