Amarogentin, a secoiridoid glycoside, activates AMP- activated protein kinase (AMPK) to exert beneficial vasculo-metabolic effects

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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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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Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation

Clinical Science ◽

10.1042/cs20180167 ◽

2018 ◽

Vol 132 (11) ◽

pp. 1155-1168 ◽

Cited By ~ 21

Author(s):

Davide Di Fusco ◽

Vincenzo Dinallo ◽

Ivan Monteleone ◽

Federica Laudisi ◽

Irene Marafini ◽

...

Keyword(s):

Protein Kinase ◽

Map Kinase ◽

Intestinal Inflammation ◽

Active Form ◽

Basic Mechanism ◽

P38 Map Kinase ◽

Metabolic Effects ◽

Kinase Activation ◽

Anti Inflammatory ◽

Amp Activated Protein Kinase

Metformin, a hypoglycemic drug used for treatment of type 2 diabetes, regulates inflammatory pathways. By using several models of intestinal inflammation, we examined whether metformin exerts anti-inflammatory effects and investigated the basic mechanism by which metformin blocks pathologic signals. Colitic mice given metformin exhibited less colonic inflammation and increased expression of active AMP-activated protein kinase, a mediator of the metabolic effects of metformin, in both epithelial and lamina propria compartments. Pharmacological inhibition of AMP-activated protein kinase reduced but did not prevent metformin-induced therapeutic effect as well as treatment of colitic mice with a pharmacological activator of AMP-activated protein kinase attenuated but did not resolve colitis. These data suggest that the anti-inflammatory effect of metformin relies on the control of additional pathways other than AMP-activated protein kinase. Indeed, metformin down-regulated p38 MAP kinase activation in colitic mice through an AMP-activated protein kinase-independent mechanism. Expression of active form of AMP-activated protein kinase was reduced in inflammatory bowel disease patients and treatment of mucosal cells of such patients with metformin enhanced AMP-activated protein kinase activation and reduced p38 MAP kinase activation, thereby inhibiting interleukin-6 expression. Our findings indicate that metformin is a good candidate for inhibiting pathological inflammation in the gut.

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Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase

Nutrients ◽

10.3390/nu13124204 ◽

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.

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Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle

Biochemical Society Transactions ◽

10.1042/bst0310196 ◽

2003 ◽

Vol 31 (1) ◽

pp. 196-201 ◽

Cited By ~ 82

Author(s):

Y. Minokoshi ◽

B.B. Kahn

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Metabolic Effects ◽

Acid Oxidation ◽

Amp Kinase ◽

Important Pathway ◽

Amp Activated Protein Kinase ◽

Stat Pathway

Leptin regulates energy homoeostasis through central and peripheral mechanisms. Initial steps in leptin action include signalling through a cytokine-like receptor which activates the JAK/STAT pathway. We investigated whether the metabolic effects of leptin in muscle could be mediated by the AMP-activated protein kinase (AMP kinase). Through studies involving leptin injection intrahypothalamically or intravenously, as well as incubation of soleus muscle or cultured muscle cells with leptin, we determined that leptin stimulates fatty acid oxidation in skeletal muscle by activating AMP kinase. Leptin exerts this effect directly at the level of muscle and also through the hypothalamic sympathetic nervous system, specifically engaging α-adrenergic receptors in muscle. This represents a novel and important pathway mediating leptin's metabolic actions.

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