Transient impairment of the adaptive response to fasting in FXR‐deficient mice

Cariou, Bertrand; Harmelen, Kirsten Van; Durán-Sandoval, Daniel; Dijk, Theo van; Grefhorst, Aldo; Bouchaert, Emmanuel; Fruchart, Jean Charles; Gonzalez, Frank J.; Kuipers, Folkert; Staels, Bart

doi:10.1016/j.febslet.2005.06.033

Cited by 79 publications

(69 citation statements)

References 18 publications

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“…Thus, FXR deficiency is not associated with impaired fat absorption under chow-fed conditions. Basal plasma glucose concentrations were significantly lower in FXR Ϫ/Ϫ mice, associated with an impaired hepatic glucose production during short term fasting (11). Plasma insulin levels were decreased in FXR Ϫ/Ϫ mice, probably reflecting an adaptive response to the relative hypoglycemia.…”

Section: Methodsmentioning

confidence: 85%

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The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice

Cariou

Harmelen

Durán-Sandoval

et al. 2006

Journal of Biological Chemistry

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488

445

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The farnesoid X receptor (FXR) is a bile acid (BA)-activated nuclear receptor that plays a major role in the regulation of BA and lipid metabolism. Recently, several studies have suggested a potential role of FXR in the control of hepatic carbohydrate metabolism, but its contribution to the maintenance of peripheral glucose homeostasis remains to be established. FXR-deficient mice display decreased adipose tissue mass, lower serum leptin concentrations, and elevated plasma free fatty acid levels. Glucose and insulin tolerance tests revealed that FXR deficiency is associated with impaired glucose tolerance and insulin resistance. Moreover, whole-body glucose disposal during a hyperinsulinemic euglycemic clamp is decreased in FXR-deficient mice. In parallel, FXR deficiency alters distal insulin signaling, as reflected by decreased insulin-dependent Akt phosphorylation in both white adipose tissue and skeletal muscle. Whereas FXR is not expressed in skeletal muscle, it was detected at a low level in white adipose tissue in vivo and induced during adipocyte differentiation in vitro. Moreover, mouse embryonic fibroblasts derived from FXR-deficient mice displayed impaired adipocyte differentiation, identifying a direct role for FXR in adipocyte function. Treatment of differentiated 3T3-L1 adipocytes with the FXR-specific synthetic agonist GW4064 enhanced insulin signaling and insulin-stimulated glucose uptake. Finally, treatment with GW4064 improved insulin resistance in genetically obese ob/ob mice in vivo. Although the underlying molecular mechanisms remain to be unraveled, these results clearly identify a novel role of FXR in the regulation of peripheral insulin sensitivity and adipocyte function. This unexpected function of FXR opens new perspectives for the treatment of type 2 diabetes.The farnesoid X receptor (FXR) 4 (NR1H4) is a nuclear receptor that is activated by bile acids (BAs) (1). A major physiological role of FXR is to protect liver cells from the deleterious effect of BA overload by decreasing their endogenous production and by accelerating BA biotransformation and excretion (1). In addition, the generation and characterization of FXR-deficient (FXR Ϫ/Ϫ ) mice has also established a critical role of FXR in lipid metabolism, since these mice display elevated serum levels of triglycerides and high density lipoprotein cholesterol (2). Recently, several studies have suggested that FXR might also regulate hepatic carbohydrate metabolism (3). The first indication came from the observation that hepatic FXR expression is reduced in several rodent models of diabetes (4). FXR expression also varies in mouse liver during nutritional changes, being increased during fasting and decreased upon refeeding (5, 6). Moreover, FXR activation by BAs or the synthetic nonsteroidal specific agonist GW4064 (7) modulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (3). However, conflicting data report either a positive (8) or a negative effect (9, 10) of BA and/or GW4064 on phosphoenolpyruvate...

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Section: Methodsmentioning

confidence: 85%

“…Indeed, FXR appears to modulate glycolytic and lipogenic pathways by interfering directly with the transcription of glucose-regulated genes, such as liver pyruvate kinase (6). Furthermore, FXR also controls the adaptive response to fasting, since FXR Ϫ/Ϫ mice exhibit transient hypoglycemia upon fasting (11).…”

mentioning

confidence: 99%

The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice

Cariou

Harmelen

Durán-Sandoval

et al. 2006

Journal of Biological Chemistry

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488

445

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“…A total of 452 genes on the arrays exhibited significant expression changes in GW4064-treated rat livers, with the expression of 239 genes being increased and 213 genes being decreased. Identified genes displaying dose-dependent expression changes upon treatment include previously well characterized FXR target genes, such as small heterodimer partner (SHP) (10,11), bile salt export pump (12), phosphoenolpyruvate carboxykinase (PEPCK) (22,33), and glucose-6-phosphatase (25). In addition, expression of a novel FXR target gene, DDAH1, was elevated in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, a number of genes regulating lipid metabolism, such as sterol response element binding protein, lipoprotein lipase, apolipoproteins E, AI, CII, and CIII, and scavenger receptor class B type I, are regulated by FXR (17-21). Furthermore, a growing body of evidence supports a role for FXR in carbohydrate metabolism (22)(23)(24)(25).Because FXR has been identified as a modulator of lipid and carbohydrate metabolism, development of a synthetic FXR agonist for treatment of dyslipidemia and diabetes, two important indicators of metabolic syndrome, appears to be an attractive therapeutic approach. The potent synthetic FXR agonist * The costs of publication of this article were defrayed in part by the payment of page charges.…”

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confidence: 99%

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Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

Chouinard

Cox

et al. 2006

Journal of Biological Chemistry

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The farnesoid X receptor (FXR, NR1H4) is a bile acid-responsive nuclear receptor that plays critical roles in the transcriptional regulation genes involved in cholesterol, bile acid, triglyceride, and carbohydrate metabolism. By microarray analysis of hepatic genes from female Zucker diabetic fatty (ZDF) rats treated with the FXR agonist GW4064, we have identified dimethylarginine dimethylaminohydrolase-1 (DDAH1) as an FXR target gene. DDAH1 is a key catabolic enzyme of asymmetric dimethylarginine (ADMA), a major endogenous nitric-oxide synthase inhibitor. Sequence analysis of the DDAH1 gene reveals the presence of an FXR response element (FXRE) located 90 kb downstream of the transcription initiation site and within the first intron. Functional analysis of the putative FXRE demonstrated GW4064 dose-dependent transcriptional activation from the element, and we have demonstrated that the FXRE sequence binds the FXR-RXR heterodimer. In vivo administration of GW4064 to female ZDF rats promoted a dose-dependent and >6-fold increase in hepatic DDAH1 gene expression. The level of serum ADMA was reduced concomitantly. These findings provide a mechanism by which FXR may increase endothelium-derived nitric oxide levels through modulation of serum ADMA levels via direct regulation of hepatic DDAH1 gene expression. Thus, beneficial clinical outcomes of FXR agonist therapy may include prevention of atherosclerosis and improvement of the metabolic syndrome.The global epidemic of obesity has led to an increasing prevalence of metabolic syndrome, a wide spectrum of metabolic risk factors characterized by abdominal obesity, low levels of high density lipoprotein cholesterol, high triglycerides, hypertension, glucose intolerance, and a systemic proinflammatory state. These risk factors are closely associated with incidence of cardiovascular disease, a leading cause of mortality in industrialized nations (1, 2). In the last decade, several ligand-activated nuclear receptors, such as peroxisome proliferator-activated receptors, liver X receptors, and thyroid hormone receptors, have emerged as promising targets for pharmacological intervention in the treatment of metabolic syndrome (3).Nuclear receptors are transcription factors that serve as intracellular sensors for endocrine hormones and lipid metabolites, such as bile acids, fatty acids, oxysterols, and xenobiotics. To control a variety of physiological processes, receptors bind to specific cis-acting DNA elements and regulate the expression of target genes by cofactor recruitment upon activation by ligands (4). Based on their pharmacological and ligand-binding properties, the nuclear receptor superfamily can be divided into three groups (5). The first group consists of classical steroid hormone receptors that are activated by high affinity ligands. The second group comprises low affinity receptors for metabolic intermediates. The third group corresponds to orphan receptors that have no known ligands.The farnesoid X receptor (FXR, 2 NR1H4) belongs to the second group of the nuc...

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Natural compounds regulate energy metabolism by the modulating the activity of lipid‐sensing nuclear receptors

Goto

Kim

Takahashi

et al. 2012

Molecular Nutrition Food Res

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Obesity causes excess fat accumulation in various tissues, most notoriously in the adipose tissue, along with other insulin-responsive organs such as skeletal muscle and the liver, which predisposes an individual to the development of metabolic abnormalities. The molecular mechanisms underlying obesity-induced metabolic abnormalities have not been completely elucidated; however, in recent years, the search for therapies to prevent the development of obesity and obesity-associated metabolic disorders has increased. It is known that several nuclear receptors, when activated by specific ligands, regulate carbohydrate and lipid metabolism at the transcriptional level. The expression of lipid metabolism-related enzymes is directly regulated by the activity of various nuclear receptors via their interaction with specific response elements in promoters of those genes. Many natural compounds act as ligands of nuclear receptors and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors. In this review, we describe our current knowledge of obesity, the role of lipid-sensing nuclear receptors in energy metabolism, and several examples of food factors that act as agonists or antagonists of nuclear receptors, which may be useful for the management of obesity and the accompanying energy metabolism abnormalities.

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Transient impairment of the adaptive response to fasting in FXR‐deficient mice

Cited by 79 publications

References 18 publications

The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice

The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice

Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

Natural compounds regulate energy metabolism by the modulating the activity of lipid‐sensing nuclear receptors

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