scholarly journals Polyphenols Stimulate AMP-Activated Protein Kinase, Lower Lipids, and Inhibit Accelerated Atherosclerosis in Diabetic LDL Receptor-Deficient Mice

Diabetes ◽  
2006 ◽  
Vol 55 (8) ◽  
pp. 2180-2191 ◽  
Author(s):  
M. Zang ◽  
S. Xu ◽  
K. A. Maitland-Toolan ◽  
A. Zuccollo ◽  
X. Hou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ldl Receptor ◽  
Accelerated Atherosclerosis ◽  
Amp Activated Protein Kinase ◽  
Deficient Mice

Enhanced Ca 2+ entry and Na + /Ca 2+ exchanger activity in dendritic cells from AMP‐activated protein kinase‐deficient mice

2012 ◽  
Vol 26 (7) ◽  
pp. 3049-3058 ◽  
Author(s):  
Meerim K. Nurbaeva ◽  
Evi Schmid ◽  
Kalina Szteyn ◽  
Wenting Yang ◽  
Benoit Viollet ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Protein Kinase ◽  
Amp Activated Protein Kinase ◽  
Deficient Mice

scholarly journals Protection Against High-Fat Diet-Induced Obesity in Helz2-Deficient Male Mice Due to Enhanced Expression of Hepatic Leptin Receptor

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3459-3472 ◽  
Author(s):  
Satoshi Yoshino ◽  
Tetsurou Satoh ◽  
Masanobu Yamada ◽  
Koshi Hashimoto ◽  
Takuya Tomaru ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
High Fat ◽  
Leptin Sensitivity ◽  
Amp Activated Protein Kinase ◽  
Central Leptin Resistance ◽  
Deficient Mice

Abstract Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.

scholarly journals Retinaldehyde Dehydrogenase 1 Coordinates Hepatic Gluconeogenesis and Lipid Metabolism

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3089-3099 ◽  
Author(s):  
Florian W. Kiefer ◽  
Gabriela Orasanu ◽  
Shriram Nallamshetty ◽  
Jonathan D. Brown ◽  
Hong Wang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Protein Kinase ◽  
Glucose Homeostasis ◽  
Retinoid Metabolism ◽  
Hepatic Glucose ◽  
Amp Activated Protein Kinase ◽  
The Impact ◽  
Deficient Mice

Recent data link vitamin A and its retinoid metabolites to the regulation of adipogenesis, insulin sensitivity, and glucose homeostasis. Retinoid metabolism is tightly controlled by an enzymatic network in which retinaldehyde dehydrogenases (Aldh1–3) are the rate-limiting enzymes that convert retinaldehyde to retinoic acid. Aldh1a1-deficient mice are protected from diet-induced obesity and hence diabetes. Here we investigated whether Aldh1a1 and the retinoid axis regulate hepatic glucose and lipid metabolism independent of adiposity. The impact of Aldh1a1 and the retinoid pathway on glucose homeostasis and lipid metabolism was analyzed in hepatocytes in vitro and in chow-fed, weight-matched Aldh1a1-deficient vs. wild-type (WT) mice in vivo. Aldh1a1-deficient mice displayed significantly decreased fasting glucose concentrations compared with WT controls as a result of attenuated hepatic glucose production. Expression of key gluconeogenic enzymes as well as the activity of Forkhead box O1 was decreased in Aldh1a1-deficient vs. WT livers. In vitro, retinoid or cAMP agonist stimulation markedly induced gluconeogenesis in WT but not Aldh1a1-deficient primary hepatocytes. Aldh1a1 deficiency increased AMP-activated protein kinase α activity, decreased expression of lipogenic targets of AMP-activated protein kinase α and significantly attenuated hepatic triacylglycerol synthesis. In metabolic cage studies, lean Aldh1a1-deficient mice manifested enhanced oxygen consumption and reduced respiratory quotient vs. WT controls, consistent with increased expression of fatty acid oxidation markers in skeletal muscle. Taken together, this work establishes a role for retinoid metabolism in glucose homeostasis in vivo and for Aldh1a1 as a novel determinant of gluconeogenesis and lipid metabolism independent of adiposity.

Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Prevents Hypoxia-Induced Tissue Injury in High Altitude By Inducing 2,3-Bisphosphoglycerate

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2664-2664
Author(s):  
Hong Liu ◽  
Yujin Zhang ◽  
Anren Song ◽  
Harry Karmouty Quintana ◽  
Almut Grenz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
High Altitude ◽  
Tissue Injury ◽  
A2b Receptor ◽  
Key Enzyme ◽  
Amp Activated Protein Kinase ◽  
Plasma Adenosine ◽  
Deficient Mice ◽  
Adenosine A2b ◽  
O2 Binding

Abstract To function effectively in O2 uptake, delivery and release, erythrocytes rely on sophisticated regulation of hemoglobin (Hb)-O2 affinity by allosteric modulators, especially 2,3-bisphophosphoglycerate (2,3-BPG). Earlier studies had shown that elevated erythrocyte 2,3-BPG level is correlated to increased availability of oxygen to tissues in high altitudes. However, nothing is known how 2,3-BPG is induced in high altitude. Recent study revealed that plasma adenosine is increased in patient and mice with sickle cell disease and elevated adenosine signaling via A2B receptor (ADORA2B) induces 2,3-BPG and thereby promotes deoxy-sickle hemoglobin and subsequent sickling. However, whether adenosine is induced and its effect in 2,3-BPG induction in high altitude are unknown. To address this question, we recruited 24 low-land volunteers and placed them in high altitude for different time points. Here we report that: 1) plasma adenosine, a molecule well known to be induced under hypoxia, is increased and its elevation is correlated to elevated erythrocyte 2,3-BPG levels and decreased Hb-O2 affinity; and 2) elevated plasma adenosine is correlated to increased circulating ecto-5’-nucleotidase (CD73), a key enzyme responsible for generation of extracellular adenosine. Similar to humans, increased circulating CD73 activity, plasma adenosine levels and erythrocyte 2,3-BPG and decreased Hb-O2 binding affinity were observed in wild type (WT) mice under hypoxia condition mimicking our human high altitude studies. Moreover, we found that hypoxia-induced increased plasma adenosine, erythrocyte 2,3-BPG and decreased Hb-O2 binding affinity were significantly attenuated in CD73-deficient mice (CD73-/-). As such, hypoxia-induced tissue injury and cell apoptosis were significantly elevated in CD73-/- mice compared to WT mice. Mechanistically, we provide both in vitro and in vivo genetic evidence that erythrocyte adenosine A2B receptor (ADORA2B) is essential for 2,3-BPG induction and subsequent O2 release. This finding led us to further discover that AMP-Activated Protein Kinase (AMPK) functions downstream of ADORA2B underlying adenosine-induced 2,3-BPG induction and O2 release by direct phosphorylation of 2,3-BPG mutase, a key enzyme for 2,3-BPG production. Finally, we demonstrated that treatment of metformin, a FDA approved potent AMPK agonist, induced erythrocyte 2,3-BPG levels and triggered O2 release and thereby prevented hypoxia-induced tissue injury in both CD73-/- mice and erythrocyte specific ADORA2B-deficient mice. Overall, our studies have revealed that erythrocyte ADORA2B-mediated AMPK activation is a novel mechanism underlying hypoxia-induced 2,3-BPG levels and thereby highlight its beneficial role to prevent hypoxia-induced tissue injury. Disclosures No relevant conflicts of interest to declare.

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