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

¹ Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
² Tupper Research Institute and Department of Medicine, Children’s Hospital Boston, Boston, Massachusetts

Address correspondence and reprint requests to Antonio C. Bianco, MD, PhD, BrighamWomen’s Hospital, 77 Avenue Louis Pasteur, HIM Bldg. #643, Boston, MA 02115. E-mail: abianco{at}partners.org

Abbreviations: cAMP, cyclic AMP; D1, type 1 deiodinase; D2, type 2 deiodinase; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HEK, human embryonic kidney; HSM, human skeletal muscle; KPF, kaempferol; MSTO, mesothelioma; mt-TFA, mitochondrial transcription factor 1; OCR, oxygen consumption rate; PGC-1, peroxisome proliferator–activated receptor coactivator 1; PKA, protein kinase A; RMS, rabdomyosarcoma; UCP, uncoupling protein; USP, ubiquitin-specific peptidase; VDU, von Hippel-Lindau protein-interacting deubiquitinating enzyme; WSB-1, suppressor of cytokine signaling [SOCS] box-containing WD-40 protein

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 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 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.

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