Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor β subtype selective agonist KB-141

Bryzgalova, Galyna; Effendic, Suad; Khan, Abdul Waheed; Rehnmark, Stefan; Barbounis, Peter; Boulet, Jamie; Dong, Gao; Singh, Rajni; Shapses, Sue A.; Malm, Johan; Webb, Paul; Baxter, John D.; Grover, Gary J.

doi:10.1016/j.jsbmb.2008.06.010

Cited by 89 publications

(70 citation statements)

References 29 publications

(65 reference statements)

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“…Previous studies from our laboratory and others have demonstrated that modulation of FGF21 levels either via pharmacology or using molecular interventions lead to a phenotype similar to that seen with TR␤ agonist treatment i.e. a significant improvement in serum lipid profile (10,22), increased rates of lipolysis, and an increase in liver fatty acid metabolism (4,32). These findings suggest that stimulation of lipolysis and hepatic fatty acid oxidation via FGF21 induction using TR␤-specific agonists has significant therapeutic potential.…”

Section: Discussionmentioning

confidence: 90%

“…Previous studies have shown that treatment with T3 itself or with selective agonists of TR␤ can improve the metabolic status of diet-induced obese rodents (22)(23)(24). Activation of TR␤ with a selective thyromimetic (GC-1) in rats results in the induction of UCP1 gene expression, whereas only minimally mediating synergism between thyroid hormone and the sympathetic nervous system (20).…”

Section: Discussionmentioning

confidence: 99%

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Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Adams

Astapova

Fisher

et al. 2010

Journal of Biological Chemistry

125

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Thyroid hormone has profound and diverse effects on liver metabolism. Here we show that tri-iodothyronine (T3) treatment in mice acutely and specifically induces hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21). Mice treated with T3 showed a dose-dependent increase in hepatic FGF21 expression with significant induction at doses as low as 100 g/kg. Time course studies determined that induction is seen as early as 4 h after treatment with a further increase in expression at 6 h after injection. As FGF21 expression is downstream of the nuclear receptor peroxisome proliferatoractivated receptor ␣ (PPAR␣), we treated PPAR␣ knock-out mice with T3 and found no increase in expression, indicating that hepatic regulation of FGF21 by T3 in liver is via a PPAR␣-dependent mechanism. In contrast, in white adipose tissue, FGF21 expression was suppressed by T3 treatment, with other T3 targets unaffected. In cell culture studies with an FGF21 reporter construct, we determined that three transcription factors are required for induction of FGF21 expression: thyroid hormone receptor ␤ (TR␤), retinoid X receptor (RXR), and PPAR␣. These findings indicate a novel regulatory pathway whereby T3 positively regulates hepatic FGF21 expression, presenting a novel therapeutic target for diseases such as non-alcoholic fatty liver disease.The biochemical pathways mediating the metabolism of carbohydrates, lipids, and proteins are all regulated to some degree by thyroid hormone and the thyroid hormone receptors (␣ and ␤) (1, 2), which belong to the nuclear hormone receptor superfamily (1). In the liver, the ␤ isoform of the thyroid hormone receptor (TR␤) is responsible for mediating the majority of the actions of tri-iodothyronine (T3), 2 whereas in other tissues such as the heart and brown adipose tissue, the ␣ isoform (TR␣) is the main mediator of thyroid hormone effects (3, 4). FGF21 is a member of the endocrine FGF subfamily, which also includes FGF19 and FGF23, all of which circulate and have hormone-like actions (5, 6). FGF21 is known to stimulate glucose uptake in mouse 3T3-L1 adipocytes and in primary cultures of human adipocytes and can improve glucose homeostasis when administered to obese mice (6) and non-human primates (7). Transgenic mice overexpressing FGF21 in liver display improved insulin sensitivity and glucose clearance, reduced plasma triglyceride concentrations, and are resistant to weight gain when fed a high fat diet (6).Subsequent studies showed that administration of FGF21 to mice with high fat diet-induced obesity led to increased fat utilization and energy expenditure and reduced plasma glucose, insulin, serum lipid concentrations, and hepatic triglyceride concentrations (6,8). In one study, it was shown that the decrease in hepatic triglyceride concentrations was accompanied by a decrease in lipogenic gene expression (8).FGF21 expression is known to be downstream of the nuclear receptor PPAR␣, which itself plays a significant role in lipid oxidation. FGF21 is physiologically induced u...

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Adams

Astapova

Fisher

et al. 2010

Journal of Biological Chemistry

125

View full text Add to dashboard Cite

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“…Another TRβ selective agonist KB-141 increased metabolic rate and lowered plasma cholesterol levels without tachycardia in lean rats. Moreover, its administration to obese Zucker fa/fa rats improved glucose tolerance and insulin sensitivity suggesting that selective TRβ activation may be a useful strategy to attenuate features of the metabolic syndrome [70].…”

Section: Trs Ligands In Treatment Of Obesitymentioning

confidence: 99%

Stimulation of Thermogenesis via Beta-Adrenergic and Thyroid Hormone Receptors Agonists in obesity Treatment Possible Reasons for Therapy Resistance

Kuryłowicz¹

2014

J Pharmacogenomics Pharmacoproteomics

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“…Interestingly, the male obese children had aberrant expression of PXR which is sensitive to endocrine "disruptors" as PXR is involved in metabolism of environmental toxins especially in the liver and THRβ, which is involved in the regulation of growth and metabolism in response to food restriction (Kudo et al, 2009, Bryzgalova et al, 2008, Amorim et al, 2009. It has been shown that PXR expression is up-regulated in TSOD (Tsumura, Suzuki, obese, diabetes) mice, a model of Type 2 Diabetes and obesity (Kudo et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that PXR expression is up-regulated in TSOD (Tsumura, Suzuki, obese, diabetes) mice, a model of Type 2 Diabetes and obesity (Kudo et al, 2009). THRβ selective agonists have recently been shown to be useful against diet-induced obesity in rodents (Bryzgalova et al, 2008, Amorim et al, 2009). In addition, the expression of several NR genes (COUP-TF1 and RARβ) that are involved in the development of obesity and metabolism were down-regulated in the male obese children but their expression were below the reliable detection limit and/or PCR failed in >50% of the cohort (data not shown).…”

Section: Discussionmentioning

confidence: 99%

A systems biology approach towards child obesity and obesity-related diseases: integration of clinical, genetic, hormonal and NMR metabonomic factors

Rahman¹

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Systems biology has become a powerful scientific method using a more holistic perspective to tackle biological and biomedical research. Complex data obtained from different types of experiments using multiple interdisciplinary tools such as metabonomics and transcriptomics can be integrated and analysed to give a better understanding of the biological problem at hand. This PhD thesis comprises closely related project parts that utilise tools of systems biology (NMR-based metabonomics, gene expression profiling, and multivariate analysis) to investigate how growth hormone deficiency (GHD) and obesity can cause alterations in metabolism of children and adolescence. In addition, method development of collecting and storage of human urine samples for NMR-based metabonomic studies were also investigated to aid in achieving accurate metabolic fingerprints. The first project established a novel standard procedure of collection, storage and preservation of human urine samples to ensure the measurement of true metabolic fingerprints in NMR-based metabonomic studies. Human urine samples are susceptible to metabolite changes when left at room temperature for less than 24 hours even with the addition of different preservatives and I have successfully established the minimum requirements to maintain the stability of urine samples for 48 hours at room temperature. Once a standard procedure of sample handling was established, a NMR-based metabonomics pilot study was performed in which the metabolic profiles of a growth hormone (GH)-deficient adolescent subject were tracked with NMR-based urinary metabonomics during five years of GH therapy . Detection of urinary metabolites related to GHD provided a clearer picture of the impact GH therapy has on metabolism. Metabonomics was able to differentiate the metabolic profiles of healthy controls from the GHD subject indicating that metabonomics has the capability to be utilised as a platform to identify the effects of GH treatment on metabolism in humans. The main project of this PhD was a study of metabolic changes in children with obesity and used tools of systems biology such as NMR-based urinary metabonomics and peripheral blood mononuclear cell (PBMC) gene expression analysis to investigate samples collected as part of the KOALA childhood obesity program. Results from both metabonomics and gene expression profiling studies were combined with clinical data using multivariate analysis (O2PLS) to provide a clearer picture of how obesity can disrupt metabolism in children. The outcome(s) of this study support the utilisation of NMR-based metabonomics as a potential diagnostic and prognostic tool not only in the context of obesity, but make the technique also available for the study of other diseases. In addition, gene expression studies of PBMCs identified significant NRs and NR-dependent pathways that may improve our understanding of the underlying molecular mechanisms in metabolic dysfunction in obesity. In summary, using tools of systems biology, a better understand can b...

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Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor β subtype selective agonist KB-141

Cited by 89 publications

References 29 publications

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Stimulation of Thermogenesis via Beta-Adrenergic and Thyroid Hormone Receptors Agonists in obesity Treatment Possible Reasons for Therapy Resistance

A systems biology approach towards child obesity and obesity-related diseases: integration of clinical, genetic, hormonal and NMR metabonomic factors

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Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor β subtype selective agonist KB-141

Cited by 89 publications

References 29 publications

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Stimulation of Thermogenesis via Beta-Adrenergic and Thyroid Hormone Receptors Agonists in obesity Treatment  Possible Reasons for Therapy Resistance

A systems biology approach towards child obesity and obesity-related diseases: integration of clinical, genetic, hormonal and NMR metabonomic factors

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Product

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Stimulation of Thermogenesis via Beta-Adrenergic and Thyroid Hormone Receptors Agonists in obesity Treatment Possible Reasons for Therapy Resistance