Molecular mechanisms of appetite and obesity: a role for brain AMPK

2016 ◽  
Vol 130 (19) ◽  
pp. 1697-1709 ◽  
Author(s):  
Pablo B. Martínez de Morentin ◽  
Adela Urisarri ◽  
María L. Couce ◽  
Miguel López
Keyword(s):  
Energy Storage ◽  
Protein Kinase ◽  
Physiological Response ◽  
Feeding Behaviour ◽  
Molecular Mechanisms ◽  
Neuronal Response ◽  
Energy Requirements ◽  
Energy Imbalance ◽  
Amp Activated Protein Kinase ◽  
The Brain

Feeding behaviour and energy storage are both crucial aspects of survival. Thus, it is of fundamental importance to understand the molecular mechanisms regulating these basic processes. The AMP-activated protein kinase (AMPK) has been revealed as one of the key molecules modulating energy homoeostasis. Indeed, AMPK appears to be essential for translating nutritional and energy requirements into generation of an adequate neuronal response, particularly in two areas of the brain, the hypothalamus and the hindbrain. Failure of this physiological response can lead to energy imbalance, ultimately with extreme consequences, such as leanness or obesity. Here, we will review the data that put brain AMPK in the spotlight as a regulator of appetite.

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.

scholarly journals GH-Releasing Hormone Induces Cardioprotection in Isolated Male Rat Heart via Activation of RISK and SAFE Pathways

Endocrinology ◽  
2013 ◽  
Vol 154 (4) ◽  
pp. 1624-1635 ◽  
Author(s):  
Claudia Penna ◽  
Fabio Settanni ◽  
Francesca Tullio ◽  
Letizia Trovato ◽  
Pasquale Pagliaro ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Male Rat ◽  
Signal Transducer ◽  
Rat Hearts ◽  
Phosphoinositide 3 Kinase ◽  
Amp Activated Protein Kinase ◽  
Transcription 3 ◽  
Isolated Rat

Abstract GHRH stimulates GH synthesis and release from the pituitary and exerts direct effects in extrapituitary tissues. We have previously shown that pretreatment with GHRH reduces cardiomyocyte apoptosis and improves heart function in isolated rat hearts subjected to ischemia/reperfusion (I/R). Here, we determined whether GHRH given at reperfusion reduces myocardial reperfusion injury and investigated the molecular mechanisms involved in GHRH effects. Isolated rat hearts subjected to I/R were treated at the onset of reperfusion with: 1) GHRH; 2) GHRH+GHRH antagonist JV-1-36; 3) GHRH+mitochondrial ATP-dependent potassium channel inhibitor 5-hydroxydecanoate; 4) GHRH+mitochondrial permeability transition pore opener atractyloside; 5) GHRH+ phosphoinositide 3-kinase/Akt inhibitor Wortmannin (WM); and 6) GHRH+signal transducer and activator of transcription-3 inhibitor tyrphostin-AG490 (AG490). GHRH reduced infarct size at the end of reperfusion and reverted contractility dysfunction in I/R hearts. These effects were inhibited by either JV-1-36, 5-hydroxydecanoate, atractylosid, WM, or AG490. Western blot analysis on left ventricles showed GHRH-induced phosphorylation of either the reperfusion injury salvage kinases (RISK), phosphoinositide 3-kinase/Akt, ERK1/2, and glycogen synthase kinase-3β or signal transducer and activator of transcription-3, as part of the survivor activating factor enhancement (SAFE) pathway. GHRH-induced activation of RISK and SAFE pathways was blocked by JV-1-36, WM, and AG490. Furthermore, GHRH increased the phosphorylation of endothelial nitric oxide synthase and AMP-activated protein kinase and preserved postischemic nicotinamide adenine dinucleotide (NAD+) levels. These results suggest that GHRH protects the heart from I/R injury through receptor-mediated mechanisms, leading to activation of RISK and SAFE pathways, which converge on mitochondria and possibly on AMP-activated protein kinase.

scholarly journals AMP-Activated Protein Kinase (AMPK) and Energy-Sensing in the Brain

2012 ◽  
Vol 21 (2) ◽  
pp. 52-60 ◽  
Author(s):  
Santosh Ramamurthy ◽  
Gabriele Ronnett
Keyword(s):  
Protein Kinase ◽  
Energy Sensing ◽  
Amp Activated Protein Kinase ◽  
The Brain

AMP-activated protein kinase in the brain

2008 ◽  
Vol 32 (S4) ◽  
pp. S42-S48 ◽  
Author(s):  
G V Ronnett ◽  
S Aja
Keyword(s):  
Protein Kinase ◽  
Amp Activated Protein Kinase ◽  
The Brain

scholarly journals Effects of AMP-Activated Protein Kinase in Cerebral Ischemia

2009 ◽  
Vol 30 (3) ◽  
pp. 480-492 ◽  
Author(s):  
Jun Li ◽  
Louise D McCullough
Keyword(s):  
Protein Kinase ◽  
In Vivo Studies ◽  
Ampk Activation ◽  
Vigorous Exercise ◽  
Nitric Oxide Signaling ◽  
Reductase Inhibitors ◽  
Amp Activated Protein Kinase ◽  
The Brain

AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK is found in most mammalian tissues including the brain. As a key metabolic and stress sensor/effector, AMPK is activated under conditions of nutrient deprivation, vigorous exercise, or heat shock. However, it is becoming increasingly recognized that changes in AMPK activation not only signal unmet metabolic needs, but also are involved in sensing and responding to ‘cell stress’, including ischemia. The downstream effect of AMPK activation is dependent on many factors, including the severity of the stressor as well as the tissue examined. This review discusses recent in vitro and in vivo studies performed in the brain/neuronal cells and vasculature that have contributed to our understanding of AMPK in stroke. Recent data on the potential role of AMPK in angiogenesis and neurogenesis and the interaction of AMPK with 3-hydroxy-3-methy-glutaryl-CoA reductase inhibitors (statins) agents are highlighted. The interaction between AMPK and nitric oxide signaling is also discussed.

scholarly journals The ubiquitin-associated domain of AMPK-related protein kinases allows LKB1-induced phosphorylation and activation

2006 ◽  
Vol 394 (3) ◽  
Author(s):  
Mark H. Rider
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Related Protein ◽  
Biochemical Journal ◽  
Kinase Catalytic Domain ◽  
Uba Domain ◽  
Amp Activated Protein Kinase

The AMPK (AMP-activated protein kinase)-related protein kinase subfamily of the human kinome comprises 12 members closely related to the catalytic α1/α2 subunits of AMPK. The precise role of the AMPK-related kinases and their in vivo substrates is rather unclear at present, but some are involved in regulating cell polarity, whereas others appear to control cellular differentiation. Of the 12 human AMPK-related protein kinase family members, 11 can be activated following phosphorylation of their T-loop threonine residue by the LKB1 complex. Nine of these AMPK-related kinases activated by LKB1 contain an UBA (ubiquitin-associated) domain immediately C-terminal to the kinase catalytic domain. In this issue of the Biochemical Journal, Jaleel et al. show that the presence of an UBA domain in AMP-related kinases allows LKB1-induced phosphorylation and activation. The findings have implications for understanding the molecular mechanisms of activation of this fascinating family of protein kinases. Also, mutations in the UBA domains of the AMP-related kinase genes might be present in families with Peutz–Jehgers syndrome and in other cancer patients.

scholarly journals LKB1 Is Physiologically Required for Sleep from Drosophila to the Mouse

2021 ◽  
Author(s):  
Ziyi Liu ◽  
Lifen Jiang ◽  
Chaoyi Li ◽  
Chengang Li ◽  
Jingqun Yang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Physiological Role ◽  
Adenosine Monophosphate ◽  
Nrem Sleep ◽  
Eeg Analysis ◽  
Loss Of Function ◽  
Sleep Regulation ◽  
Amp Activated Protein Kinase ◽  
The Brain ◽  
Mediated Reduction

LKB1 is known as a master kinase for 14 kinases related to the adenosine monophosphate (AMP)-activated protein kinase (AMPK). Two of them (SIK3 and AMPKa;) have previously been implicated in sleep regulation. We generated loss-of-function (LOF) mutants for Lkb1 in both Drosophila and mice. Sleep was reduced in Lkb1-mutant flies and in flies with neuronal deletion of Lkb1. Sleep was reduced in mice after virally mediated reduction of Lkb1 in the brain. Electroencephalography (EEG) analysis showed that non-rapid eye movement (NREM) sleep and sleep need were both reduced in Lkb1-mutant mice. These results indicate that LKB1 plays a physiological role in sleep regulation conserved from flies to mice.

Insulin-Like Growth Factor 1/Mammalian Target of Rapamycin and AMP-Activated Protein Kinase Signaling Involved in the Effects of Metformin in the Human Endometrial Cancer

2016 ◽  
Vol 26 (9) ◽  
pp. 1667-1672 ◽  
Author(s):  
Dongge Cai ◽  
Hongli Sun ◽  
Yanhua Qi ◽  
Xiaogui Zhao ◽  
Minjuan Feng ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Growth Factor ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Pilot Trial ◽  
Plasma Concentrations ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Insulin Like Growth Factor ◽  
Amp Activated Protein Kinase

BackgroundMetformin is a well-tolerated biguanide drug used for decades to treat type 2 diabetes mellitus. In recent years, long-term administration of metformin has been found to reduce carcinogenic risk for cancers derived from various tissues. However, its cellular and molecular mechanisms of anticancer action in the endometrial cancer (EC) have not yet been fully elucidated.Patients and MethodsSixty patients diagnosed as endometrial carcinoma were grouped into (n = 30) and non-treatment mixed (n = 30) for analysis. Thirty healthy donors are control groups. We attempt to investigate the interaction of metformin, insulin-like growth factor 1 (IGF-1) expression, and phosphorylated mammalian target of rapamycin (p-mTOR) and AMP-activated protein kinase (p-AMPK).ResultsWe found that high IGF-1 plasma concentrations in women with EC were reversed by conventional antidiabetic doses of metformin in the present work. In parallel, the activation of AMPK and suppression of mTOR seemed to play an important role for the effect of metformin in patients with EC.ConclusionsThis pilot trial presents biological evidence consistent with antiproliferative effects of metformin in women with EC in the clinical setting.

Abstract 568: Deletion of AMP-activated Protein Kinase-alpha Triggers Mitochondrial Fission and Endothelial Dysfunction

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Qqilong Wang ◽  
Zhonglin Xie ◽  
Huaiping Zhu ◽  
Ye Ding ◽  
Ming-Hui Zou
Keyword(s):  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Chronic Administration ◽  
Mitochondrial Fragmentation ◽  
Aortic Endothelium ◽  
Amp Activated Protein Kinase

Introduction: AMP-activated protein kinase (AMPK) has been reported to regulate mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which AMPK regulates mitochondrial dynamics remain poorly characterized. We hypothesized that AMPK deficiency regulates mitochondrial fission that will result in endothelial dysfunction. Methods/Results: Deletion of AMPKα2 resulted in defective autophagy, dynamin-related protein (Drp1) accumulation, and aberrant mitochondrial fragmentation in the aortic endothelium of mice. Furthermore, autophagy inhibition by chloroquine treatment or Atg7 small interfering RNA (siRNA) transfection upregulated Drp1 expression and triggered Drp1-mediated mitochondrial fragmentation. In contrast, autophagy activation by overexpression of Atg7 or chronic administration of rapamycin, the mammalian target of rapamycin kinase inhibitor, promoted Drp1 degradation and attenuated mitochondrial fission in AMPKα2 -/- mice, suggesting that defective autophagy contributes to enhanced Drp1 expression and mitochondrial fragmentation. Interesting, the genetic (Drp1 siRNA) or pharmacological (mdivi-1) inhibition of Drp1 ablated mitochondrial fragmentation in the mouse aortic endothelium and prevented the acetylcholine-induced relaxation of isolated mouse aortas from AMPKα2 -/- mice. This suggests that aberrant Drp1 is responsible for enhanced mitochondrial fission and endothelial dysfunction in AMPKα knockout mice. Conclusions: Our results show that AMPKα deletion promoted mitochondrial fission in vascular endothelial cells by inhibiting the autophagy-dependent degradation of Drp1.

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