TRC150094, a novel functional analog of iodothyronines, reduces adiposity by increasing energy expenditure and fatty acid oxidation in rats receiving a high‐fat diet

Cioffi, Federica; Zambad, S. P.; Chhipa, Laxmikant; Senese, Rosalba; Busiello, Rosa Anna; Tuli, Davinder; Munshi, Siralee; Moreno, María; Lombardi, Assunta; Gupta, Ramesh C.; Chauthaiwale, Vijay; Dutt, Chaitanya; Lange, Pieter de; Silvestri, Elena; Lanni, Antonia; Goglia, Fernando

doi:10.1096/fj.10-157115

Cited by 40 publications

(51 citation statements)

References 34 publications

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“…8). Supporting our data were the observations that a T 3 analog, TRC150094, did not increase SIRT1 protein abundance, although there was elevated SIRT1 activity (43).…”

Section: Discussionsupporting

confidence: 84%

Role of Sirtuin 1 in the Regulation of Hepatic Gene Expression by Thyroid Hormone

Thakur

Sharma

Attia

et al. 2013

Journal of Biological Chemistry

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Background: Sirtuin 1 elevates the expression of genes involved in hepatic fatty acid oxidation. Results: Sirtuin 1 modulates the thyroid hormone regulation of the cpt1a, pdk4, and srebp-1c genes. Conclusion: Sirtuin 1 coregulates the thyroid hormone receptor-mediated induction of gene expression. Significance: Activators of sirtuin 1 and thyroid hormone receptor ␤ agonists could cooperatively stimulate fatty acid oxidation and inhibit lipogenesis.

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“…8). Supporting our data were the observations that a T 3 analog, TRC150094, did not increase SIRT1 protein abundance, although there was elevated SIRT1 activity (43).…”

Section: Discussionsupporting

confidence: 84%

Role of Sirtuin 1 in the Regulation of Hepatic Gene Expression by Thyroid Hormone

Thakur

Sharma

Attia

et al. 2013

Journal of Biological Chemistry

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“…A feature of 'nonreceptor-mediated' mechanisms of iodothyronines is the plurality of TH derivatives, including T 2 , or of functional analogs that may initiate specific actions and might have higher potency than T 3 (Cioffi et al 2010b). The ability of THs to regulate energy utilization as well as their role in promoting mitochondrial uncoupling of substrate oxidation from ATP synthesis have been long recognized.…”

Section: Discussionmentioning

confidence: 99%

Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

Grasselli

Voci

Canesi

et al. 2011

Journal of Endocrinology

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Iodothyronines influence lipid metabolism and energy homeostasis. Previous studies demonstrated that 3,5-L-diiodothyronine (T 2 ), as well as 3,3 0 ,5-L-triiodothyronine (T 3 ), was able to both prevent and reverse hepatic steatosis in rats fed a high-fat diet, and this effect depends on a direct action of iodothyronines on the hepatocyte. However, the involvement of thyroid hormone receptors (TRs) in mediating the lipid-lowering effect of iodothyronines was not elucidated. In this study, we investigated the ability of T 2 and T 3 to reduce the lipid overloading using the rat hepatoma FaO cells defective for functional TRs. The absence of constitutive mRNA expression of both TRa1 and TRb1 in FaO cells was verified by RT-qPCR. To mimic the fatty liver condition, FaO cells were treated with a fatty acid mixture and then exposed to pharmacological doses of T 2 or T 3 for 24 h. Lipid accumulation, mRNA expression of the peroxisome proliferator-activated receptors (PPAR-a, -g, -d) the acyl-CoA oxidase (AOX), and the stearoyl CoA desaturase (SCD1), as well as fuel-stimulated O 2 consumption in intact cells, were evaluated. Lipid accumulation was associated with an increase in triacylglycerol content, PPARg mRNA expression, and a decrease in PPARd and SCD1 mRNA expression. The addition of T 2 or T 3 to lipid-overloaded cells resulted in i) reduction in lipid content; ii) downregulation of PPARa, PPARg, and AOX expression; iii) increase in PPARd expression; and iv) stimulation of mitochondrial uncoupling. These data demonstrate, for the first time, that in the hepatocyte, the lipid-lowering actions of both T 2 and T 3 are not mediated by TRs.

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“…On the other hand, SRT1720, a SIRT1-specific activator that attenuated the deleterious effects of high-fat diet intake, mostly by triggering lipid oxidation in metabolic active tissues, as skeletal muscle, liver, and BAT (Feige et al 2008), and, specifically in BAT, SRT1720 were also able to increase TRa and TRb mRNA expression (Feige et al 2008). In addition, both T 2 and TRC150094, a pharmacological functional analog of T 2 , reduced deleterious metabolic effects of highfat diet in rats, and the mechanism may be related to their ability to increase SIRT1 activity in the liver (Cioffi et al 2010, de Lange et al 2011. Interestingly, pituitary SIRT1 is preferentially co-localized with TSH cells and SIRT1 overexpression and knockdown in pituitary cells resulted in increased and decreased TSH secretion respectively (Akieda-Asai et al 2010).…”

Section: Sirt1 Regulation By Th Involves Trbmentioning

confidence: 96%

Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice

Cordeiro¹,

Souza²,

Oliveira³

et al. 2012

Journal of Endocrinology

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Sirtuin 1 (SIRT1), a NAD C -dependent deacetylase, has been connected to beneficial effects elicited by calorie restriction. Physiological adaptation to starvation requires higher activity of SIRT1 and also the suppression of thyroid hormone (TH) action to achieve energy conservation. Here, we tested the hypothesis that those two events are correlated and that TH may be a regulator of SIRT1 expression. Forty-eight-hour fasting mice exhibited reduced serum TH and increased SIRT1 protein content in liver and brown adipose tissue (BAT), and physiological thyroxine replacement prevented or attenuated the increment of SIRT1 in liver and BAT of fasted mice. Hypothyroid mice exhibited increased liver SIRT1 protein, while hyperthyroid ones showed decreased SIRT1 in liver and BAT. In the liver, decreased protein is accompanied by reduced SIRT1 activity and no alteration in its mRNA. Hyperthyroid and hypothyroid mice exhibited increases and decreases in food intake and body weight gain respectively. Food-restricted hyperthyroid animals (pair-fed to euthyroid group) exhibited liver and BAT SIRT1 protein levels intermediary between euthyroid and hyperthyroid mice fed ad libitum. Mice with TH resistance at the liver presented increased hepatic SIRT1 protein and activity, with no alteration in Sirt1 mRNA. These results suggest that TH decreases SIRT1 protein, directly and indirectly, via food ingestion control and, in the liver, this reduction involves TRb. The SIRT1 reduction induced by TH has important implication to integrated metabolic responses to fasting, as the increase in SIRT1 protein requires the fasting-associated suppression of TH serum levels.

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TRC150094, a novel functional analog of iodothyronines, reduces adiposity by increasing energy expenditure and fatty acid oxidation in rats receiving a high‐fat diet

Cited by 40 publications

References 34 publications

Role of Sirtuin 1 in the Regulation of Hepatic Gene Expression by Thyroid Hormone

Role of Sirtuin 1 in the Regulation of Hepatic Gene Expression by Thyroid Hormone

Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice

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