Bezafibrate, a Peroxisome Proliferator-Activated Receptors Agonist, Decreases Body Temperature and Enhances Electroencephalogram Delta-Oscillation during Sleep in Mice

Chikahisa, Sachiko; Tominaga, Kikuo; Kawai, Tomoko; Kitaoka, Katsuhiko; Oishi, Katsutaka; Ishida, Norio; Rokutan, Kazuhito; Séi, Hiroyoshi

doi:10.1210/en.2008-0285

Cited by 55 publications

(53 citation statements)

References 39 publications

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“…PPAR␣ has also been implicated in a variety of metabolic processes including lipid metabolism and energy homeostasis (1,2), affecting many of the pathways in response to fasting, such as gluconeogenesis, ketogenesis, and fatty acid metabolism. Recent studies showed that FGF21, the endocrine hormone synthesized from a liver PPAR␣ target gene (36), is able to enter into the brain through the blood-brain barrier and up-regulate hypothalamic NPY (37,38). In the present study, fasting and PPAR␣ agonist administration both induced liver FGF21, which confirms previous observations (2,39).…”

Section: Discussionsupporting

confidence: 91%

Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor α and Role of the Hypothalamic-Pituitary-Adrenal Axis

Wang

Shah

Matsubara

et al. 2010

Journal of Biological Chemistry

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A previous study identified the peroxisome proliferator-activated receptor ␣ (PPAR␣) activation biomarkers 21-steroid carboxylic acids 11␤-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11␤,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA). In the present study, the molecular mechanism and the metabolic pathway of their production were determined. The PPAR␣-specific time-dependent increases in HDOPA and 20␣-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPAR␣ induced hepatic FGF21, which caused increased neuropeptide Y and agouti-related protein mRNAs in the hypothalamus, stimulation of the agouti-related protein/neuropeptide Y neurons, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased adrenal cortex hyperplasia and corticosterone production, revealing a link between PPAR␣ and the HPA axis in controlling energy homeostasis and immune regulation. Corticosterone was demonstrated as the precursor of 21-carboxylic acids both in vivo and in vitro. Under PPAR␣ activation, the classic reductive metabolic pathway of corticosterone was suppressed, whereas an alternative oxidative pathway was uncovered that leads to the sequential oxidation on carbon 21 resulting in HDOPA. The latter was then reduced to the end product 20␣-DHOPA. Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPAR␣ resulted in the induction of Aldh3a2 and Akr1c18, both of which were confirmed as target genes through introduction of promoter luciferase reporter constructs into mouse livers in vivo.This study underscores the power of mass spectrometry-based metabolomics combined with genomic and physiologic analyses in identifying downstream metabolic biomarkers and the corresponding upstream molecular mechanisms. Peroxisome proliferator-activated receptor ␣ (PPAR␣)7 is a nuclear hormone receptor regulating a number of physiologic processes including lipid metabolism and energy homeostasis via the transactivation of various target genes (1, 2). In a previous study (3), 11␤-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11␤,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA), two specific biomarkers of PPAR␣ activation, were identified through urinary ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry (UPLC-TOFMS)-based metabolomics analysis of wild-type and Pparanull mice fed either a regular diet or a diet containing the PPAR␣ ligand Wy-14,643 (WY). However, the issue remained of defining the metabolic pathway and identifying the target genes involved in the synthesis of these two biomarkers. Although metabolomics has been actively applied to investigate physiological/pathological biomarkers via the robust analytical ability to discriminate small molecule metabolomes in biofluids, cells, tissues, and organisms (4, 5), its power for translatio...

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Section: Discussionsupporting

confidence: 91%

Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor α and Role of the Hypothalamic-Pituitary-Adrenal Axis

Wang

Shah

Matsubara

et al. 2010

Journal of Biological Chemistry

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“…The plausible mechanism by which fat oxidation increases NREM sleep is an increase in plasma concentration of ketone bodies. Another study in mice reported that increases of the plasma ketone ratio (acetoacetate/b-hydroxybutyrate) were associated with increased EEG delta power in NREM sleep (26), which has been used as physiological markers of deep sleep and homeostatic need for sleep (27). Plasma ketone bodies were not measured in the present study, but it is reasonable to expect their increase after HFD consumption (28).…”

Section: Discussionmentioning

confidence: 99%

Effects of Nutrient Composition of Dinner on Sleep Architecture and Energy Metabolism during Sleep

Yajima

Seya

Iwayama

et al. 2014

J Nutr Sci Vitaminol

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Summary Energy metabolism and substrate oxidation during sleep correlate with sleep stage, suggesting that energy metabolism affects sleep architecture or vice versa. The aim of the present study was to examine whether changes in energy metabolism during sleep, induced by a high-carbohydrate or high-fat meal for dinner, affect sleep architecture. Ten healthy males participated in this study, sleeping 3 nonconsecutive nights in a whole-room calorimeter. The first night was scheduled as an adaptation to the experimental environment. The other 2 nights were experimental calorimetry in a balanced cross-over design with intrasubject comparisons. In each session, subjects comsumed a high carbohydrate (HCD: PFC510 : 10 : 80) or high fat (HFD: PFC510 : 78 : 12) meal at 2000 h and slept with a polysomnographic recording in a metabolic chamber for indirect calorimetry (0000 h to 0800 h). Slow wave sleep was decreased during the first sleep cycle and not changed during the second or third sleep cycle under HCD conditions compared with those of HFD. Energy expenditure was not affected by dietary condition but substrate oxidation reflected differences in dietary composition of the dinner during the first and second sleep cycle. The present study suggested the possibility that substrate availability during sleep affects substrate oxidation during sleep, and affects sleep architecture during the first sleep cycle.

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“…FGF21 administration increases NPY mRNA levels in the hypothalamus (Coskun et al 2008). Similarly, treatment of mice with a fibrate PPAR agonist induces hypothermia, accompanied by increased NPY expression in the hypothalamus, and an NPY-Y1 receptor antagonist prevents this fibrate-mediated hypothermia (Chikahisa et al 2008). However, neither PPARa nor FGF21 is essential for fasting-mediated induction of NPY (Oishi et al 2010).…”

Section: Physiological Actions Of Fgf21mentioning

confidence: 99%

Endocrine fibroblast growth factors 15/19 and 21: from feast to famine

Potthoff¹,

Kliewer²,

Mangelsdorf³

2012

Genes Dev.

396

403

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We review the physiology and pharmacology of two atypical fibroblast growth factors (FGFs)-FGF15/19 and FGF21-that can function as hormones. Both FGF15/19 and FGF21 act on multiple tissues to coordinate carbohydrate and lipid metabolism in response to nutritional status. Whereas FGF15/19 is secreted from the small intestine in response to feeding and has insulin-like actions, FGF21 is secreted from the liver in response to extended fasting and has glucagon-like effects. FGF21 also acts in an autocrine fashion in several tissues, including adipose. The pharmacological actions of FGF15/19 and FGF21 make them attractive drug candidates for treating metabolic disease.The discovery of hormones such as insulin and glucagon that regulate metabolism has a long and storied history. The field of endocrinology continues to be invigorated by the discovery of new metabolic hormones. Among the relatively recent additions are three fibroblast growth factors (FGFs), termed FGF15/19, FGF21, and FGF23. (FGF15 and FGF19 are the mouse and human orthologs, respectively, which we refer to as FGF15/19 unless specifically referring to one species or the other.) In contrast to most FGFs, which act in an autocrine or paracrine fashion, the three ''endocrine FGFs'' can be released into the bloodstream to act throughout the body. While the fundamental role that FGF23 plays in regulating phosphate metabolism has been known for more than a decade (White et al. 2000;Shimada et al. 2001), the discovery of FGF15/19 and FGF21 and their wide-ranging effects on carbohydrate and lipid metabolism has been more recent. This review focuses on FGF15/19 and FGF21.

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Bezafibrate, a Peroxisome Proliferator-Activated Receptors Agonist, Decreases Body Temperature and Enhances Electroencephalogram Delta-Oscillation during Sleep in Mice

Cited by 55 publications

References 39 publications

Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor α and Role of the Hypothalamic-Pituitary-Adrenal Axis

Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor α and Role of the Hypothalamic-Pituitary-Adrenal Axis

Effects of Nutrient Composition of Dinner on Sleep Architecture and Energy Metabolism during Sleep

Endocrine fibroblast growth factors 15/19 and 21: from feast to famine

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