Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family ...receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.
AMPK-Mediated AS160 Phosphorylation in Skeletal Muscle Is Dependent on AMPK Catalytic and Regulatory Subunits
Jonas T. Treebak 1 ,
Stephan Glund 2 ,
Atul Deshmukh 2 ,
Ditte K. Klein 1 ,
Yun Chau Long ...2 ,
Thomas E. Jensen 1 ,
Sebastian B. Jørgensen 1 ,
Benoit Viollet 3 ,
Leif Andersson 4 ,
Dietbert Neumann 5 ,
Theo Wallimann 5 ,
Erik A. Richter 1 ,
Alexander V. Chibalin 2 ,
Juleen R. Zierath 2 and
Jørgen F.P. Wojtaszewski 1
1 Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of
Copenhagen, Copenhagen, Denmark
2 Department of Molecular Medicine and Surgery, Section Integrative Physiology, Karolinska Institute, Stockholm, Sweden
3 René Descartes University, Institute Cochin, Paris, France
4 Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala Biomedical Center, Uppsala, Sweden
5 Swiss Federal Institute of Technology, Zurich, Switzerland
Address correspondence and reprint requests to Juleen R. Zierath, Department of Molecular Medicine and Surgery, Section for
Integrative Physiology, Karolinska Institute, von Eulers väg 4, 4th Floor, S-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}ki.se
Abstract
AMP-activated protein kinase (AMPK) is a heterotrimeric protein that regulates glucose transport mediated by cellular stress
or pharmacological agonists such as 5-aminoimidazole-4-carboxamide 1 β- d -ribonucleoside (AICAR). AS160, a Rab GTPase-activating protein, provides a mechanism linking AMPK signaling to glucose uptake.
We show that AICAR increases AMPK, acetyl-CoA carboxylase, and AS160 phosphorylation by insulin-independent mechanisms in
isolated skeletal muscle. Recombinant AMPK heterotrimeric complexes (α1β1γ1 and α2β2γ1) phosphorylate AS160 in a cell-free
assay. In mice deficient in AMPK signaling (α2 AMPK knockout KO, α2 AMPK kinase dead KD, and γ3 AMPK KO), AICAR effects
on AS160 phosphorylation were severely blunted, highlighting that complexes containing α2 and γ3 are necessary for AICAR-stimulated
AS160 phosphorylation in intact skeletal muscle. Contraction-mediated AS160 phosphorylation was also impaired in α2 AMPK KO
and KD but not γ3 AMPK KO mice. Our results implicate AS160 as a downstream target of AMPK.
ACC, acetyl-CoA carboxylase
AICAR, 5-aminoimidazole-4-carboxamide 1 β-d-ribonucleoside
AMPK, AMP-activated protein kinase
CaMKK, calmodulin-dependent protein kinase kinase
EDL, extensor digitorum longus
GST, glutathione S-transferase
PAS, phospho-Akt substrate
TSC, tuberous sclerosis complex
Footnotes
J.T.T., S.G., and A.D. contributed equally to this work.
See related article by Kramer et al., p. 2067.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact
Accepted March 23, 2006.
Received February 7, 2006.
DIABETES
On aligning curves Sebastian, T.B.; Klein, P.N.; Kimia, B.B.
IEEE transactions on pattern analysis and machine intelligence,
2003-Jan., 2003-01-00, 20030101, Volume:
25, Issue:
1
Journal Article
Peer reviewed
We present a novel approach to finding a correspondence (alignment) between two curves. The correspondence is based on a notion of an alignment curve which treats both curves symmetrically. We then ...define a similarity metric based on the alignment curve using two intrinsic properties of the curve, namely, length and curvature. The optimal correspondence is found by an efficient dynamic-programming method both for aligning pairs of curve segments and pairs of closed curves, and is effective in the presence of a variety of transformations of the curve. Finally, the correspondence is shown in application to handwritten character recognition, prototype formation, and object recognition, and is potentially useful in other applications such as registration and tracking.
Psychological science remains unclear about how individuals' trait perfectionism impacts their performance—is more perfectionism linearly better or does too perfect backfire? The present study ...investigates a potentially non-linear relationship and its underlying mediators. Based on the two-dimensional model of perfectionism that distinguishes perfectionistic concerns (PC) versus strivings (PS), we investigate the (non-)linear relationships of perfectionism and performance in the letter detection task. Additionally, we experimentally examined whether time pressure would moderate these findings. Our study results (N = 229) establish non-linearity: a quadratic function in the form of an inverted U-shape best explains the relationship between perfectionistic concerns and performance. Contrary to our hypothesis, perfectionistic strivings predicted task performance linearly but negatively. Upon further examination, we also found empirical support for a combinatory effect of both dimensions: Only individuals high in PC showed the negative effect of PS on task performance. Although performance differed in the timed versus untimed task, time pressure did not moderate the (non-)linear relationships of PS or PC on performance. Multiple mediation analyses revealed that perceived distress, rumination, and effort mediated the quadratic relationships of perfectionistic concerns. Overall, our results question the strict disentanglement of perfectionistic dimensions and emphasise the usefulness of a more holistic approach.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Systemic mastocytosis is a neoplastic disease of mast cells harboring the activating KIT mutation D816V. In most patients, mast cell infiltration in the bone marrow is accompanied by marked ...microenvironment alterations, including increased angiogenesis, osteosclerosis, and sometimes fibrosis. Little is known about the mast cell-derived molecules contributing to these bone marrow alterations. We show here that neoplastic mast cells in patients with systemic mastocytosis express oncostatin M (OSM), a profibrogenic and angiogenic modulator. To study the regulation of OSM expression, KIT D816V was inducibly expressed in Ba/F3 cells and was found to up-regulate OSM mRNA and protein levels, suggesting that OSM is a KIT D816V-dependent mediator. Correspondingly, KIT D816V+ HMC-1.2 cells expressed significantly higher amounts of OSM than the KIT D816V− HMC-1.1 subclone. RNA interference-induced knockdown of STAT5, a key transcription factor in KIT D816V+ mast cells, inhibited OSM expression in HMC-1 cells, whereas a constitutively activated STAT5 mutant induced OSM expression. Finally, OSM secreted from KIT D816V+ mast cells stimulated growth of endothelial cells, fibroblasts, and osteoblasts, suggesting that mast cell-derived OSM may serve as a key modulator of the marrow microenvironment and thus contribute to the pathology of systemic mastocytosis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this report, 528 cases of monkeypox across 16 countries are described. Rash, mucosal lesions, fever, lethargy, and lymphadenopathy were common clinical findings. Few patients were hospitalized.
Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using ...quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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