The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue

Jesus, Lucia A. de; Carvalho, Suzy D.; Ribeiro, Miriam O.; Schneider, Mark J.; Kim, Sung Woo; Harney, John W.; Larsen, P. Reed; Bianco, Antonio C.

doi:10.1172/jci200113803

Cited by 428 publications

(242 citation statements)

References 52 publications

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“…Focus was then turned to the KPF induction of Dio2. D2 is an important component of the thermogenic gene expression profile in stimulated BAT and probably in HSM (3,(21)(22)(23). First, we verified that Dio2 induction by KPF resulted in a 8.5-to 50-fold increase in D2 activity in more than one cell line, including HSM myoblasts, MSTO-211H cells, and RMS-13 cells (Fig.…”

Section: Resultssupporting

confidence: 61%

“…Our approach has included a screen of potential xenobiotic molecules, i.e., small molecules from plants that trigger biological effects in other organisms, for the ability to increase D2 activity. D2 activity and thyroid hormone T3 production in intact cells were selected as surrogates for induction of the metabolic rate because D2 induction is known to be part of a thermogenic program in brown adipocytes (3) and because D2-mediated T3 production in certain settings could directly contribute to energy expenditure (2). Furthermore, methods for measurement of D2 activity and T3 production are easily performed and could be easily scaled up for screening studies.…”

mentioning

confidence: 99%

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The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

et al. 2007

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Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an ϳ30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor ␥ coactivator-1␣, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an ϳ10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of ϳ2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans. Diabetes 56:767-776, 2007

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Section: Resultssupporting

confidence: 61%

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confidence: 99%

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

et al. 2007

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“…Cold-exposed D2KO mice are deficient in brown adipocyte T3 production resulting in reduced lipolysis and lipogenesis, leading to an impairment of BAT thermogenesis. D2KO mice survive cold exposure by a compensatory increase in shivering, which requires a marked increase in total body fuel consumption (47,48).…”

Section: Deiodinases and Metabolic Controlmentioning

confidence: 99%

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Marsili

Zavacki

Harney

et al. 2011

J Endocrinol Invest

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Thyroxine (T4) is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue-specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights.

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“…Elovl3 , which is highly induced by rosiglitazone treatment, 21 displayed substantial induction (at least 77-fold) in every serum batch analyzed (Figure 4G); no overall difference could be seen between FBS and NCS (Figure 4H). Dio2 , highly induced in BAT in the cold, 36,37 displayed little change in response to rosiglitazone (Figure 4IJ). …”

Section: Resultsmentioning

confidence: 98%

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes

2018

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Much current understanding of brown adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type (“fetal bovine” versus “newborn calf”) on responses to differentiation inducers (the PPARγ agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary brown adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion (Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3) was not systematically affected by serum type. However, importantly, acute (2 h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in brown adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.

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The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue

Cited by 428 publications

References 52 publications

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes

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