Rapid reversal of hepatic steatosis, and reduction of muscle triglyceride, by rosiglitazone: MRI/S studies in Zucker fatty rats

Hockings, Paul D.; Changani, K. Kumar; Saeed, Noha M.; Reid, David G.; Birmingham, J.; O’Brien, Peter J.; Osborne, J. A.; Toseland, C. N.; Buckingham, Robin E.

doi:10.1046/j.1463-1326.2003.00268.x

Cited by 65 publications

(47 citation statements)

References 58 publications

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“…However, there is mounting evidence that rosiglitazone acts to improve insulin sensitivity in the absence of decreased muscle lipid storage in humans (9,27) and animal models of insulin resistance (7,10,12,28), suggesting that lipid steal from muscle may not be necessary for rosiglitazone-induced insulin sensitization. Although some investigations have demonstrated that lipid storage is decreased in muscle after rosiglitazone treatment (3,4,24), rosiglitazone-induced reductions of liver lipid accumulation have been more consistently observed (5,7,9,29). In the present study, 4-week rosiglitazone treatment resulted in a 20% increase in muscle TAG content (Fig.…”

Section: Fig 3 Skeletal Muscle Ampk Activity and Protein Expressionsupporting

confidence: 37%

“…It has been suggested that peroxisome proliferator-activated receptor (PPAR) agonists, such as rosiglitazone, improve skeletal muscle insulin sensitivity by preventing the toxic accumulation of lipids in this tissue (3,4). However, the sequestration of lipids from skeletal muscle after chronic rosiglitazone treatment has not been consistently observed (3)(4)(5)(6)(7)(8)(9)(10)(11). There is also evidence that mechanism(s) independent of changes in lipid status (i.e., skeletal muscle AMP-activated protein kinase [AMPK] activation) may be involved in the insulinsensitizing actions of rosiglitazone (12,13).…”

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confidence: 99%

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Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance

et al. 2007

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Both pharmacological intervention (i.e., thiazolidinediones [TZDs]) and lifestyle modification (i.e., exercise training) are clinically effective treatments for improving whole-body insulin sensitivity. However, the mechanism(s) by which these therapies reverse lipid-induced insulin resistance in skeletal muscle is unclear. We determined the effects of 4 weeks of rosiglitazone treatment and exercise training and their combined actions (rosiglitazone treatment and exercise training) on lipid and glucose metabolism in high-fat-fed rats. High-fat feeding resulted in decreased muscle insulin sensitivity, which was associated with increased rates of palmitate uptake and the accumulation of the fatty acid metabolites ceramide and diacylglycerol. Impairments in lipid metabolism were accompanied by defects in the Akt/AS160 signaling pathway. Exercise training, but not rosiglitazone treatment, reversed these impairments, resulting in improved insulinstimulated glucose transport and increased rates of fatty acid oxidation in skeletal muscle. The improvements to glucose and lipid metabolism observed with exercise training were associated with increased AMP-activated protein kinase ␣1 activity; increased expression of Akt1, peroxisome proliferator-activated receptor ␥ coactivator 1, and GLUT4; and a decrease in AS160 expression. In contrast, rosiglitazone treatment exacerbated lipid accumulation and decreased insulin-stimulated glucose transport in skeletal muscle. However, rosiglitazone, but not exercise training, increased adipose tissue GLUT4 and acetyl CoA carboxylase expression. Both exercise training and rosiglitazone decreased liver triacylglycerol content. Although both interventions can improve whole-body insulin sensitivity, our results show that they produce divergent effects on protein expression and triglyceride storage in different tissues. Accordingly, exercise training and rosiglitazone may act as complementary therapies for the treatment of insulin resistance.

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Section: Fig 3 Skeletal Muscle Ampk Activity and Protein Expressionsupporting

confidence: 37%

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confidence: 99%

Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance

et al. 2007

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“…In trained athletes this relationship was reversed and high IMCL predicted high insulin sensitivity. In recent years, 1 H-MRS of IMCL has been increasingly used in animals, in particular to study pharmacological interventions and at higher magnetic field strength (23)(24)(25)(26)(27)(28). It would go beyond the target of this review to go into methodological details of these studies since MR examinations in small animals with voxels of a few microliters pose different methodological challenges than MRS in humans.…”

Section: Relation Between Imcl Content and Insulin Sensitivitymentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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1 H-MR spectroscopy (MRS) of intramyocellular lipids (IMCL) became particularly important when it was recognized that IMCL levels are related to insulin sensitivity. While this relation is rather complex and depends on the training status of the subjects, various other influences such as exercise and diet also influence IMCL concentrations. This may open insight into many metabolic interactions; however, it also requires careful planning of studies in order to control all these confounding influences. This review summarizes various historical, methodological, and practical aspects of 1 H-MR spectroscopy (MRS) of muscular lipids. That includes a differentiation of bulk magnetic susceptibility effects and residual dipolar coupling that can both be observed in MRS of skeletal muscle, yet affecting different metabolites in a specific way. Fitting of the intra-(IMCL) and extramyocellular (EMCL) signals with complex line shapes and the transformation into absolute concentrations is discussed. Since the determination of IMCL in muscle groups with oblique fiber orientation or in obese subjects is still difficult, potential improvement with high-resolution spectroscopic imaging or at higher field strength is considered. Fat selective imaging is presented as a possible alternative to MRS and the potential of multinuclear MRS is discussed. 1 H-MRS of muscle lipids allows non-invasive and repeated studies of muscle metabolism that lead to highly relevant findings in clinics and patho-physiology.

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“…Proton MRS methods have been used widely to characterize triacylglycerols and other fatty acids in tissue and tissue extracts (27)(28)(29)(30), and numerous MRS studies of liver lipids in humans have been described (18,(31)(32)(33)(34). MRS measurements of liver fat levels in rats have been reported previously (35,36). However, the wide variety of transgenic species available and the homology between mouse and human genomes make the mouse more appropriate for studying a variety of diseases than is the rat.…”

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confidence: 98%

In vivo MRS measurement of liver lipid levels in mice

Garbow

Lin

Sakata

et al. 2004

Journal of Lipid Research

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A magnetic resonance spectroscopy (MRS) procedure for in vivo measurement of lipid levels in mouse liver is described and validated. The method uses respiratory-gated, localized spectroscopy to collect proton spectra from voxels within the mouse liver. Bayesian probability theory analysis of these spectra allows the relative intensities of the lipid and water resonances within the liver to be accurately measured. All spectral data were corrected for measured spin-spin relaxation. A total of 48 mice were used in this study, including wild-type mice and two different transgenic mouse strains. Different groups of these mice were fed high-fat or low-fat diets or liquid diets with and without the addition of alcohol. Proton spectra were collected at baseline and, subsequently, Alcoholic (1, 2) and nonalcoholic fatty liver (NAFL) (3-7) are highly prevalent in human populations and may develop into steatohepatitis and in some cases into cirrhosis requiring liver transplantation. Animal models of both conditions have been developed. Mouse models are particularly useful because genetic manipulations are highly developed in inbred mice. However, longitudinal studies require the killing of animals because no noninvasive method for quantifying liver fat is available. Here, we describe a noninvasive, nondestructive method for quantifying the liver fat contents of the mouse using a NAFL mouse model. The overwhelming majority of NAFL cases are associated with obesity, dyslipidemia, hypertension, insulin-resistant type 2 diabetes mellitus, and atherosclerotic cardiovascular disease (8)(9)(10)(11)(12). This constellation defines the metabolic syndrome (13,14). One naturally occurring cause of fatty liver is familial hypobetalipoproteinemia (FHBL). FHBL is defined by less than fifth percentile plasma levels of LDL-cholesterol and/or total apolipoprotein B (apoB), segregating in families as an autosomal dominant trait (15-17). The mean liver triglyceride content in apoBimpaired FHBL subjects is 3-to 5-fold greater than that of controls (18,19).In an attempt to understand the cellular/molecular bases of hypobetalipoproteinemia, several recombinant mice mimicking human FHBL have been produced (19)(20)(21)(22)(23)(24)(25). The resulting mice closely resemble their human counterparts with respect to the fatty liver phenotype. Thus, these mice could serve as good models of one genetic form of fatty liver for studies of the progression of fatty liver and on the effects of metabolic, hormonal, and therapeutic perturbations over time.One current limitation of such studies is the absence of an accurate, quantifiable, noninvasive method for repeat assessments of liver fat in animals. In humans, the gold standard for quantifying liver fat is the liver biopsy, which is invasive and, at best, semiquantitative. The analogous procedure in animals is killing of the animal and direct analysis of liver fat by standard chemical methods after extraction. Obviously, direct sampling of livers for fat analysis is not ideal for longitudinal, fol...

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Rapid reversal of hepatic steatosis, and reduction of muscle triglyceride, by rosiglitazone: MRI/S studies in Zucker fatty rats

Abstract: Localized MRS and MRI showed that rosiglitazone reversed the hepatic steatosis, hepatomegaly and intramyocellular lipid, characteristic of the ZF rat, an animal model of obesity.

Cited by 65 publications

References 58 publications

Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance

Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance

Role of proton MR for the study of muscle lipid metabolism

In vivo MRS measurement of liver lipid levels in mice

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