Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes

Murakami, Ryuichiro; Murakami, Hisashi; Kataoka, Hirokatsu; Cheng, Xian Wu; Takahashi, Ryōsuke; Numaguchi, Yasushi; Murohara, Toyoaki; Okumura, Kenji

doi:10.1016/j.lfs.2010.09.005

Cited by 6 publications

(8 citation statements)

References 25 publications

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“…As we have shown that fenofibric acid exhibits minimal activity at cannabinoid receptors, any effects of fenofibrate on cannabinoid receptors after absorption appear unlikely. However, Murakami et al (34) reported that fenofibrate, but not fenofibric acid, increased AMP kinase phosphorylation in hepatoma cells, and oral administration of fenofibrate to C3H mice also increased the phosphorylation of AMP kinase in the liver, but not in skeletal muscle, indicating that unmetabolized fenofibrate accumulates in the liver. These results suggest that it is unlikely that the AMP kinase phosphorylation effect of fenofibrate was PPAR‐α mediated, and it would be interesting to determine whether it might be due to CB receptor activation.…”

Section: Discussionmentioning

confidence: 98%

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

et al. 2014

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Cannabinoids are reported to have actions through peroxisome proliferator-activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. Radio-ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB 1 ) or cannabinoid type 2 (CB 2 ) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-a agonist fenofibrate exhibited submicromolar affinity for both receptors (pK i CB 1 , 6.3 6 0.1; CB 2 , 7.7 6 0.1). Functionally, fenofibrate acted as an agonist at the CB 2 receptor (pEC 50 , 7.7 6 0.1) and a partial agonist at the CB 1 receptor, although with a decrease in functional response at higher concentrations, producing bell-shaped concentration-response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for [ 3 H]-CP55940 at the CB 1 receptor, (k fast without: 1.2 6 0.2/min; with: 3.8 6 0.1 3 10 22 /min) and decrease the maximal response to CP55940 (R max , 86 6 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB 1 receptors (pEC 50 , 6.0 6 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target.-Priestley, R. S., Nickolls, S. A., Alexander, S. P. H., Kendall, D. A. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate.

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Section: Discussionmentioning

confidence: 98%

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

et al. 2014

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“…Activation of AMPK is involved in the increase of skeletal muscle fatty acid oxidation and insulin dependent glucose transport induced by physical exercise (Sriwijitkamol et al, ). On the other hand, Murakami et al () have reported treatment with a higher dose of fenofibrate (200 mg/Kg BW/day) induces AMPK activation in the liver but not in skeletal muscle of C3H mice. Even though fenofibrate did not activate AMPK, it reduces lipid storage in skeletal muscle.…”

Section: Discussionmentioning

confidence: 98%

“…Therefore, this drug may inhibit glucose production in the liver. In fact, fenofibrate decreases activity of phosphoenolpyruvate carboxykinase (PEPCK) and gluconeogenesis in the liver (Cornwell, De Souza, & Ulrich, ; Dana et al, ; Matsuura et al, ; Murakami et al, ; Srivastava, ).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of AMPK is involved in the increase of skeletal muscle fatty acid oxidation and insulin dependent glucose transport induced by physical exercise (Sriwijitkamol et al, 2007). On the other hand, Murakami et al (2010) In spite of treatment of DIO rodents with fenofibrate has been reported to suppress weight gain and reduce visceral adiposity ameliorating metabolic disorder, the mechanisms by which fenofibrate exerts these effects have yet to be completely elucidated (Chaput, Saladin, Silvestre, & Edgar, 2000;Goto et al, 2017;Liu et al, 2014;Mancini et al, 2001;Rachid et al, 2015). The postulated mechanism involved in anti-obesity effect of fenofibrate is a browning effect on subcutaneous fat depots (Rachid et al, 2015) via the increase in hepatic FGF21 (Goto et al, 2017).…”

Section: Fenofibrate Effects On Muscle Insulin Sensitivity and Lipimentioning

confidence: 99%

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Fenofibrate reverses changes induced by high‐fat diet on metabolism in mice muscle and visceral adipocytes

Frias

Rocha

Mendonça

et al. 2017

Journal Cellular Physiology

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The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.

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“…Furthermore, in control rats, fenofibrate decreased liver glycogen. Inhibition of liver gluconeogenesis, without changes in muscle glucose metabolism after fenofibrate, has been reported (32). These authors proposed that fenofibrate may have a favorable effect on glucose metabolism by inhibiting gluconeogenesis in the liver and maintaining systemic lipid and insulin-dependent muscle glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate administration to arthritic rats increases adiponectin and leptin and prevents oxidative muscle wasting

Castillero¹,

Martín

Nieto-Bona

et al. 2012

Endocrine Connections

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Chronic inflammation induces skeletal muscle wasting and cachexia. In arthritic rats, fenofibrate, a peroxisome proliferator-activated receptor α (PPARα (PPARA)) agonist, reduces wasting of gastrocnemius, a predominantly glycolytic muscle, by decreasing atrogenes and myostatin. Considering that fenofibrate increases fatty acid oxidation, the aim of this study was to elucidate whether fenofibrate is able to prevent the effect of arthritis on serum adipokines and on soleus, a type I muscle in which oxidative metabolism is the dominant source of energy. Arthritis was induced by injection of Freund's adjuvant. Four days after the injection, control and arthritic rats were gavaged daily with fenofibrate (300 mg/kg bw) or vehicle over 12 days. Arthritis decreased serum leptin, adiponectin, and insulin (P<0.01) but not resistin levels. In arthritic rats, fenofibrate administration increased serum concentrations of leptin and adiponectin. Arthritis decreased soleus weight, cross-sectional area, fiber size, and its Ppar α mRNA expression. In arthritic rats, fenofibrate increased soleus weight, fiber size, and Ppar α expression and prevented the increase in Murf1 mRNA. Fenofibrate decreased myostatin, whereas it increased MyoD (Myod1) and myogenin expressions in the soleus of control and arthritic rats. These data suggest that in oxidative muscle, fenofibrate treatment is able to prevent arthritis-induced muscle wasting by decreasing Murf1 and myostatin expression and also by increasing the myogenic regulatory factors, MyoD and myogenin. Taking into account the beneficial action of adiponectin on muscle wasting and the correlation between adiponectin and soleus mass, part of the anticachectic action of fenofibrate may be mediated through stimulation of adiponectin secretion.

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Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes

Cited by 6 publications

References 25 publications

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

A potential role for cannabinoid receptors in the therapeutic action of fenofibrate

Fenofibrate reverses changes induced by high‐fat diet on metabolism in mice muscle and visceral adipocytes

Fenofibrate administration to arthritic rats increases adiponectin and leptin and prevents oxidative muscle wasting

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