The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation

Wagner S. Da-Silva, John W. Harney, Brian W. Kim, Jing Li, Suzy D C Bianco, Alessandra Crescenzi, Marcelo A. Christoffolete, Stephen A. Huang, Antonio C. Bianco

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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 ∼30% 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 γ coactivator-1α, 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 ∼10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of ∼2.6-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.

Original languageEnglish
Pages (from-to)767-776
Number of pages10
JournalDiabetes
Volume56
Issue number3
DOIs
StatePublished - Mar 1 2007

Fingerprint

Thyroid Hormones
Energy Metabolism
Cyclic AMP
Skeletal Myoblasts
Genes
Adenylate Kinase
Citrate (si)-Synthase
Iodide Peroxidase
Bucladesine
Peroxisome Proliferator-Activated Receptors
kaempferol
Carnitine
Metabolic Diseases
Skeletal Muscle Fibers
Quercetin
Triiodothyronine
Xenobiotics
Transferases
Cyclic AMP-Dependent Protein Kinases
Metabolic Networks and Pathways

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Da-Silva, W. S., Harney, J. W., Kim, B. W., Li, J., Bianco, S. D. C., Crescenzi, A., ... Bianco, A. C. (2007). The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes, 56(3), 767-776. https://doi.org/10.2337/db06-1488

The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. / Da-Silva, Wagner S.; Harney, John W.; Kim, Brian W.; Li, Jing; Bianco, Suzy D C; Crescenzi, Alessandra; Christoffolete, Marcelo A.; Huang, Stephen A.; Bianco, Antonio C.

In: Diabetes, Vol. 56, No. 3, 01.03.2007, p. 767-776.

Research output: Contribution to journalArticle

Da-Silva, WS, Harney, JW, Kim, BW, Li, J, Bianco, SDC, Crescenzi, A, Christoffolete, MA, Huang, SA & Bianco, AC 2007, 'The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation', Diabetes, vol. 56, no. 3, pp. 767-776. https://doi.org/10.2337/db06-1488
Da-Silva, Wagner S. ; Harney, John W. ; Kim, Brian W. ; Li, Jing ; Bianco, Suzy D C ; Crescenzi, Alessandra ; Christoffolete, Marcelo A. ; Huang, Stephen A. ; Bianco, Antonio C. / The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. In: Diabetes. 2007 ; Vol. 56, No. 3. pp. 767-776.
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