AMP-Activated Protein Kinase-Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

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Sex Differences in the Metabolic Effects of Testosterone in Sheep

Endocrinology ◽

10.1210/en.2011-1634 ◽

2012 ◽

Vol 153 (1) ◽

pp. 123-131 ◽

Cited By ~ 19

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.

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Endogenous Ligand for GPR120, Docosahexaenoic Acid, Exerts Benign Metabolic Effects on the Skeletal Muscles via AMP-activated Protein Kinase Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m115.657379 ◽

2015 ◽

Vol 290 (33) ◽

pp. 20438-20447 ◽

Cited By ~ 34

Author(s):

Nami Kim ◽

Jung Ok Lee ◽

Hye Jeong Lee ◽

Hyung Ip Kim ◽

Joong Kwan Kim ◽

...

Keyword(s):

Protein Kinase ◽

Docosahexaenoic Acid ◽

Skeletal Muscles ◽

Metabolic Effects ◽

Endogenous Ligand ◽

Amp Activated Protein Kinase ◽

Kinase Pathway

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

Endocrinology ◽

10.1210/en.2013-2160 ◽

2014 ◽

Vol 155 (9) ◽

pp. 3459-3472 ◽

Cited By ~ 7

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.

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

Diabetes ◽

10.2337/db05-1188 ◽

2006 ◽

Vol 55 (8) ◽

pp. 2180-2191 ◽

Cited By ~ 449

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

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Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway

Diabetologia ◽

10.1007/s00125-011-2079-7 ◽

2011 ◽

Vol 54 (6) ◽

pp. 1491-1501 ◽

Cited By ~ 91

Author(s):

C. Zhang ◽

C. McFarlane ◽

S. Lokireddy ◽

S. Bonala ◽

X. Ge ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Signalling Pathway ◽

Amp Activated Protein Kinase ◽

Protein Kinase Signalling ◽

Deficient Mice

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StimulatingS-adenosyl-l-methionine synthesis extends lifespan via activation of AMPK

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1604047113 ◽

2016 ◽

Vol 113 (42) ◽

pp. 11913-11918 ◽

Cited By ~ 15

Author(s):

Takafumi Ogawa ◽

Ryohei Tsubakiyama ◽

Muneyoshi Kanai ◽

Tetsuya Koyama ◽

Tsutomu Fujii ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Protein Kinase ◽

Cell Survival ◽

Metabolic Effects ◽

Model Organisms ◽

Lifespan Extension ◽

Beneficial Effects ◽

Energy Sensing ◽

Amp Activated Protein Kinase ◽

Methionine Synthesis

Dietary restriction (DR), such as calorie restriction (CR) or methionine (Met) restriction, extends the lifespan of diverse model organisms. Although studies have identified several metabolites that contribute to the beneficial effects of DR, the molecular mechanism underlying the key metabolites responsible for DR regimens is not fully understood. Here we show that stimulatingS-adenosyl-l-methionine (AdoMet) synthesis extended the lifespan of the budding yeastSaccharomyces cerevisiae. The AdoMet synthesis-mediated beneficial metabolic effects, which resulted from consuming both Met and ATP, mimicked CR. Indeed, stimulating AdoMet synthesis activated the universal energy-sensing regulator Snf1, which is theS. cerevisiaeortholog of AMP-activated protein kinase (AMPK), resulting in lifespan extension. Furthermore, our findings revealed thatS-adenosyl-l-homocysteine contributed to longevity with a higher accumulation of AdoMet only under the severe CR (0.05% glucose) conditions. Thus, our data uncovered molecular links between Met metabolites and lifespan, suggesting a unique function of AdoMet as a reservoir of Met and ATP for cell survival.

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