scholarly journals Shedding light on the intricate puzzle of ghrelin's effects on appetite regulation

2009 ◽  
Vol 202 (2) ◽  
pp. 191-198 ◽  
Author(s):  
Blerina Kola ◽  
Márta Korbonits
Keyword(s):  
Uncoupling Protein ◽  
Metabolic Effects ◽  
Metabolic Enzyme ◽  
Appetite Regulation ◽  
Calmodulin Kinase ◽  
Wide Range ◽  
Upstream Kinase ◽  
Ampk Activity ◽  
Acid Pathway ◽  
Amp Activated Protein Kinase

Ghrelin, a hormone primarily produced by the stomach, has a wide range of metabolic and non-metabolic effects. It also stimulates food intake through activation of various hypothalamic and brain stem neurons. A series of recent studies have explored the intracellular mechanisms of the appetite-inducing effect of ghrelin in the hypothalamus, shedding light on the intricate mechanisms of appetite regulation. AMP-activated protein kinase (AMPK) is a key metabolic enzyme involved in appetite regulation. Calmodulin kinase kinase 2 (CaMKK2) has been identified as an upstream kinase of AMPK and a key mediator in the effect of ghrelin on AMPK activity. The fatty acid pathway, hypothalamic mitochondrial respiration, and uncoupling protein 2 have been outlined as downstream targets of AMPK and mediators of ghrelin's appetite stimulating effect. This short overview summarises the present data in this field.

scholarly journals Sex Differences in the Metabolic Effects of Testosterone in Sheep

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Scott D. Clarke ◽  
Iain J. Clarke ◽  
Alexandra Rao ◽  
Michael A. Cowley ◽  
Belinda A. Henry
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Uncoupling Protein ◽  
Specific Effect ◽  
Metabolic Effects ◽  
Mrna Levels ◽  
Nonesterified Fatty Acids ◽  
Glucose Levels ◽  
Amp Activated Protein Kinase ◽  
The Brain

Adiposity is regulated in a sexually divergent manner. This is partly due to sex steroids, but the differential effects of androgens in males and females are unclear. We investigated effects of testosterone on energy balance in castrated male (n = 6) and female sheep (n = 4), which received 3 × 200 mg testosterone implants for 2 wk or blank implants (controls). Temperature probes were implanted into retroperitoneal fat and skeletal muscle. Blood samples were taken to measure metabolites and insulin. In males, muscle and fat biopsies were collected to measure uncoupling protein (UCP) mRNA and phosphorylation of AMP-activated protein kinase and Akt. Testosterone did not change food intake in either sex. Temperature in muscle was higher in males than females, and testosterone reduced heat production in males only. In fat, however, temperature was higher in the castrate males compared with females, and there was no effect of testosterone treatment in either sex. Preprandial glucose levels were lower, but nonesterified fatty acids were higher in females compared with males, irrespective of testosterone. In males, the onset of feeding increased UCP1 and UCP3 mRNA levels in skeletal muscle, without an effect of testosterone. During feeding, testosterone reduced glucose levels in males only but did not alter the phosphorylation of AMP-activated protein kinase or Akt in muscle. Thus, testosterone maintains lower muscle and fat temperatures in males but not females. The mechanism underlying this sex-specific effect of testosterone is unknown but may be due to sexual differentiation of the brain centers controlling energy expenditure.

Hypoxia and AMP independently regulate AMP-activated protein kinase activity in heart

2005 ◽  
Vol 288 (5) ◽  
pp. H2412-H2421 ◽  
Author(s):  
Markus Frederich ◽  
Li Zhang ◽  
James A. Balschi
Keyword(s):  
Protein Kinase ◽  
Metabolic Inhibitors ◽  
Protein Kinase Activity ◽  
Α Subunit ◽  
Rat Hearts ◽  
Upstream Kinase ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The hypothesis was tested that hypoxia increases AMP-activated protein kinase (AMPK) activity independently of AMP concentration ([AMP]) in heart. In isolated perfused rat hearts, cytosolic [AMP] was changed from 0.2 to 16 μM using metabolic inhibitors during both normal oxygenation (95% O2-5% CO2, normoxia) and limited oxygenation (95% N2-5% CO2, hypoxia). Total AMPK activity measured in vitro ranged from 2 to 40 pmol·min−1·mg protein−1 in normoxic hearts and from 5 to 55 pmol·min−1·mg protein−1 in hypoxic hearts. The dependence of the in vitro total AMPK activity on the in vivo cytosolic [AMP] was determined by fitting the measurements from individual hearts to a hyperbolic equation. The [AMP] resulting in half-maximal total AMPK activity ( A0.5) was 3 ± 1 μM for hypoxic hearts and 28 ± 13 μM for normoxic hearts. The A0.5 for α2-isoform AMPK activity was 2 ± 1 μM for hypoxic hearts and 13 ± 8 μM for normoxic hearts. Total AMPK activity correlated with the phosphorylation of the Thr172 residue of the AMPK α-subunit. In potassium-arrested hearts perfused with variable O2 content, α-subunit Thr172 phosphorylation increased at O2 ≤ 21% even though [AMP] was <0.3 μM. Thus hypoxia or O2 ≤ 21% increased AMPK phosphorylation and activity independently of cytosolic [AMP]. The hypoxic increase in AMPK activity may result from either direct phosphorylation of Thr172 by an upstream kinase or reduction in the A0.5 for [AMP].

Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles

2003 ◽  
Vol 95 (3) ◽  
pp. 960-968 ◽  
Author(s):  
Masataka Suwa ◽  
Hiroshi Nakano ◽  
Shuzo Kumagai
Keyword(s):  
Enzyme Activities ◽  
Uncoupling Protein ◽  
Capillary Density ◽  
Metabolic Effects ◽  
Antioxidant Enzyme Activities ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Characteristics ◽  
Edl Muscle ◽  
Amp Activated Protein Kinase

This study was designed to determine the histological and metabolic effects of the administration of 5′-AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 14 successive days. AICAR treatment caused a significant decrease in the percentage of type IIB fibers and the concomitant increase in the percentage of type IIX fibers in extensor digitorum longus (EDL) muscle. The capillary density and the capillary-to-fiber ratio were not altered by AICAR. AICAR treatment increased the glycolytic and oxidative enzyme activities but not the antioxidant enzyme activities. The AICAR treatment increased the uncoupling protein 3 (UCP3) level in EDL and the peroxisome proliferator-activated receptor-γ coactivator-1α protein level in the soleus and EDL muscles, whereas the myogenin level was not altered by AICAR. These results seem to imply that the chronic activation of AMPK alters such muscle histochemical and metabolic characteristics.

scholarly journals Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4204
Author(s):  
Valentina Capelli ◽  
Carmen Grijota-Martínez ◽  
Nathalia R. V. Dragano ◽  
Eval Rial-Pensado ◽  
Johan Fernø ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Core Body Temperature ◽  
Metabolic Effects ◽  
Central Administration ◽  
Treatment Protocols ◽  
Brown Adipose ◽  
Amp Activated Protein Kinase

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.

scholarly journals Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662

2014 ◽  
Vol 306 (6) ◽  
pp. E688-E696 ◽  
Author(s):  
Serge Ducommun ◽  
Rebecca J. Ford ◽  
Laurent Bultot ◽  
Maria Deak ◽  
Luc Bertrand ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Metabolic Diseases ◽  
Cellular Tissue ◽  
Intact Cells ◽  
Downstream Signaling ◽  
Upstream Kinase ◽  
A Cell ◽  
Single Compound ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a key cellular energy sensor and regulator of metabolic homeostasis. Activation of AMPK provides beneficial outcomes in fighting against metabolic disorders such as insulin resistance and type 2 diabetes. Currently, there is no allosteric AMPK activator available for the treatment of metabolic diseases, and limited compounds are available to robustly stimulate cellular/tissue AMPK in a specific manner. Here we investigated whether simultaneous administration of two different pharmacological AMPK activators, which bind and act on different sites, would result in an additive or synergistic effect on AMPK and its downstream signaling and physiological events in intact cells. We observed that cotreating primary hepatocytes with the AMP mimetic 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) and a low dose (1 μM) of the allosteric activator A769662 produced a synergistic effect on AMPK Thr172 phosphorylation and catalytic activity, which was associated with a more profound increase/decrease in phosphorylation of downstream AMPK targets and inhibition of hepatic lipogenesis compared with single-compound treatment. Mechanistically, we found that cotreatment does not stimulate LKB1, upstream kinase for AMPK, but it protects against dephosphorylation of Thr172 phosphorylation by protein phosphatase PP2Cα in an additive manner in a cell-free assay. Collectively, we demonstrate that AICAR sensitizes the effect of A769662 and promotes AMPK activity and its downstream events. The study demonstrates the feasibility of promoting AMPK activity by using two activators with distinct modes of action in order to achieve a greater activation of AMPK and downstream signaling.

scholarly journals AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic β cells, and may regulate insulin release

1998 ◽  
Vol 335 (3) ◽  
pp. 533-539 ◽  
Author(s):  
Ian P. SALT ◽  
Gabriele JOHNSON ◽  
Stephen J. H. ASHCROFT ◽  
D. Grahame HARDIE
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Insulin Release ◽  
Cell Lines ◽  
Cell Types ◽  
Β Cell ◽  
Upstream Kinase ◽  
Ampk Activity ◽  
Two Parameters ◽  
Amp Activated Protein Kinase

The role of the AMP-activated protein kinase (AMPK) cascade in the glucose-sensitive pancreatic β cell lines HIT-T15 and INS-1 was addressed. In both cell types, removal of glucose leads to a > 5-fold activation of AMPK activity. Activation of AMPK was due to phosphorylation, since the effect was reversed by protein phosphatase treatment of the extracts, and was restored by re-addition of MgATP and the purified upstream kinase. When the effects of different concentrations of medium glucose were examined, insulin secretion and AMPK activity were inversely related, and varied over the same concentration range. The activation in response to glucose removal appeared to be due to changes in the concentration of the known regulators of the cascade, i.e. AMP and ATP, since AMPK activation was associated with a large increase in the cellular AMP/ATP ratio, and the two parameters varied over the same range of glucose concentrations. In late-passage HIT-T15 cells that had lost the glucose-dependent insulin secretion response, both AMPK activity and the AMP/ATP ratio also became insensitive to the extracellular glucose concentration. Treatment of INS-1 cells, but not HIT-T15 cells, with AICA riboside (5-aminoimidazole-4-carboxamide riboside) results in accumulation of the ribotide, ZMP (AICA riboside monophosphate), and activation of AMPK. AICA riboside treatment of INS-1 cells, and of isolated rat islets, had both inhibitory and stimulatory effects on insulin secretion. These results show that in β cell lines the AMP-activated protein kinase, like its yeast homologue the SNF1 complex, can respond to the level of glucose in the medium, and may be involved in regulating insulin release.

scholarly journals Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter

2021 ◽  
Author(s):  
Danielle L Schmitt ◽  
Stephanie D Curtis ◽  
Allen Leung ◽  
Jin-fan Zhang ◽  
Mingyuan Chen ◽  
...  
Keyword(s):  
Dynamic Range ◽  
High Sensitivity ◽  
Dynamic Activity ◽  
Ampk Signaling ◽  
Upstream Kinase ◽  
Cellular Energetics ◽  
Liver Kinase B1 ◽  
Ampk Activity ◽  
Nuclear Shuttling ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics which coordinates metabolism by phosphorylating a plethora of substrates throughout the cell. But whether AMPK activity is regulated at different subcellular locations to provide precise spatial and temporal control over metabolism is unclear. Genetically encoded AMPK activity reporters (AMPKAR) have provided a window into spatial AMPK activity, but the limited dynamic range of current AMPKARs hinders detailed study. To monitor the dynamic activity of AMPK with high sensitivity, we developed a single-fluorophore AMPK activity reporter (ExRai AMPKAR) that exhibits an excitation ratiometric fluorescence change upon phosphorylation by AMPK, with over 3-fold greater response compared to previous AMPKARs. Using subcellularly localized ExRai AMPKAR, we found that the activity of AMPK at the lysosome and mitochondria are differentially regulated. While different activating conditions, irrespective of their effects on ATP, robustly yet gradually increase mitochondrial AMPK activity, lysosomal AMPK activity accumulates with much faster kinetics. Genetic deletion of the canonical upstream kinase liver kinase B1 (LKB1) resulted in slower AMPK activity at lysosomes but did not affect the response amplitude at either location, in sharp contrast to the necessity of LKB1 for maximal cytoplasmic AMPK activity. We further discovered AMPK activity in the nucleus, which resulted from LKB1-mediated cytoplasmic activation of AMPK followed by nuclear shuttling. Thus, a new, sensitive reporter for AMPK activity, ExRai AMPKAR, in complement with mathematical and biophysical methods, captured subcellular AMPK activity dynamics in living cells and unveiled complex regulation of AMPK signaling within subcellular compartments.

scholarly journals AMPK activation by A-769662 and 991 does not affect catecholamine-induced lipolysis in human adipocytes

2018 ◽  
Vol 315 (5) ◽  
pp. E1075-E1085 ◽  
Author(s):  
Franziska Kopietz ◽  
Christine Berggreen ◽  
Sara Larsson ◽  
Johanna Säll ◽  
Mikael Ekelund ◽  
...  
Keyword(s):  
Lipolytic Activity ◽  
Human Adipose Tissue ◽  
Hormone Sensitive Lipase ◽  
Metabolic Effects ◽  
Ampk Activation ◽  
Human Adipocytes ◽  
Important Regulator ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Activation of AMP-activated protein kinase (AMPK) is considered an attractive strategy for the treatment of type 2 diabetes. Favorable metabolic effects of AMPK activation are mainly observed in skeletal muscle and liver tissue, whereas the effects in human adipose tissue are only poorly understood. Previous studies, which largely employed the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), suggest an antilipolytic role of AMPK in adipocytes. The aim of this work was to reinvestigate the role of AMPK in the regulation of lipolysis, using the novel allosteric small-molecule AMPK activators A-769662 and 991, with a focus on human adipocytes. For this purpose, human primary subcutaneous adipocytes were treated with A-769662, 991, or AICAR, as a control, before being stimulated with isoproterenol. AMPK activity status, glycerol release, and the phosphorylation of hormone-sensitive lipase (HSL), a key regulator of lipolysis, were then monitored. Our results show that both A-769662 and 991 activated AMPK to a level that was similar to, or greater than, that induced by AICAR. In contrast to AICAR, which as expected was antilipolytic, neither A-769662 nor 991 affected lipolysis in human adipocytes, although 991 treatment led to altered HSL phosphorylation. Furthermore, we suggest that HSL Ser660 is an important regulator of lipolytic activity in human adipocytes. These data suggest that the antilipolytic effect observed with AICAR in previous studies is, at least to some extent, AMPK independent.

scholarly journals Expression of Uncoupling Protein 3 and GLUT4 Gene in Skeletal Muscle of Preterm Newborns: Possible Control by AMP-Activated Protein Kinase

2006 ◽  
Vol 60 (5) ◽  
pp. 569-575 ◽  
Author(s):  
Petr Brauner ◽  
Pavel Kopecky ◽  
Pavel Flachs ◽  
Ondrej Kuda ◽  
Jaroslav Vorlicek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Uncoupling Protein ◽  
Uncoupling Protein 3 ◽  
Amp Activated Protein Kinase ◽  
Preterm Newborns

scholarly journals Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin

2007 ◽  
Vol 192 (3) ◽  
pp. 605-614 ◽  
Author(s):  
Fang Cai ◽  
Armen V Gyulkhandanyan ◽  
Michael B Wheeler ◽  
Denise D Belsham
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Cell Model ◽  
Neuronal Cell ◽  
Cell Types ◽  
Glucose Sensing ◽  
Protein Kinase Activity ◽  
Energy Status ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The mammalian hypothalamus comprises an array of phenotypically distinct cell types that interpret peripheral signals of energy status and, in turn, elicits an appropriate response to maintain energy homeostasis. We used a clonal representative hypothalamic cell model expressing proopiomelanocortin (POMC; N-43/5) to study changes in AMP-activated protein kinase (AMPK) activity and glucose responsiveness. We have demonstrated the presence of cellular machinery responsible for glucose sensing in the cell line, including glucokinase, glucose transporters, and appropriate ion channels. ATP-sensitive potassium channels were functional and responded to glucose. The N-43/5 POMC neurons may therefore be an appropriate cell model to study glucose-sensing mechanisms in the hypothalamus. In N-43/5 POMC neurons, increasing glucose concentrations decreased phospho-AMPK activity. As a relevant downstream effect, we found that POMC transcription increased with 2.8 and 16.7 mM glucose. Upon addition of leptin, with either no glucose or with 5 mM glucose, we found that leptin decreased AMPK activity in N-43/5 POMC neurons, but had no significant effect at 25 mM glucose, whereas insulin decreased AMPK activity at only 5 mM glucose. These results demonstrate that individual hypothalamic neuronal cell types, such as the POMC neuron, can have distinct responses to peripheral signals that relay energy status to the brain, and will therefore be activated uniquely to control neuroendocrine function.

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