**10. Conclusion**

Energy expenditure by TH has long been realized to be accounted for by uncoupling of mitochondrial oxidative phosphorylation. However, the mode-of-action of TH in promoting mitochondrial uncoupling remained elusive. Mitochondrial uncoupling by TH is transduced by TH-induced gating of mitochondrial PTP due to modulating its Bcl2-family proteins. This mode-of-action underscores the physiological aspects of mitochondrial PTP in modulating metabolic rate, in contrast to most previous studies that analyzed mitochondrial PTP in its apoptotic context. TH-induced gating of mitochondrial PTP may offer a whole new dimension of developing novel anti-obesity drugs that promote weight loss by targeting mitochondrial PTP.

Thyroid Hormone and Energy Expenditure 287

[10] Brand MD, Steverding D, Kadenbach B, Stevenson PM, Hafner RP. The mechanism of the increase in mitochondrial proton permeability induced by thyroid hormones. Eur J

[11] Kalderon B, Hertz R, Bar-Tana J. Effect of thyroid hormone treatment on redox and

[12] Pehowich DJ. Thyroid hormone status and membrane n-3 fatty acid content influence mitochondrial proton leak. Biochim Biophys Acta. 1999 Apr 21;1411(1):192-200. [13] Nobes CD, Lakin-Thomas PL, Brand MD. The contribution of ATP turnover by the Na+/K+-ATPase to the rate of respiration of hepatocytes. Effects of thyroid status and

[14] Shears SB, Bronk JR. The influence of thyroxine administered in vivo on the transmembrane protonic electrochemical potential difference in rat liver mitochondria.

[15] Gregory RB, Berry MN. The administration of triiodothyronine to rats results in a lowering of the mitochondrial membrane potential in isolated hepatocytes. Biochim

[16] Harper ME, Brand MD. The quantitative contributions of mitochondrial proton leak and ATP turnover reactions to the changed respiration rates of hepatocytes from rats of

[17] Mihara S, Suzuki N, Wakisaka S, Suzuki S, Sekita N, Yamamoto S, et al. Effects of thyroid hormones on apoptotic cell death of human lymphocytes. J Clin Endocrinol

[18] Shulman GI, Ladenson PW, Wolfe MH, Ridgway EC, Wolfe RR. Substrate cycling between gluconeogenesis and glycolysis in euthyroid, hypothyroid, and hyperthyroid

[19] Freake HC, Oppenheimer JH. Thermogenesis and thyroid function. Annu Rev Nutr.

[20] Muller MJ, Seitz HJ. Rapid and direct stimulation of hepatic gluconeogenesis by Ltriiodothyronine (T3) in the isolated-perfused rat liver. Life Sci. 1980 Sep 8;27(10):827-35. [21] Sestoft L. Metabolic aspects of the calorigenic effect of thyroid hormone in mammals.

[22] Oppenheimer JH, Koerner D, Schwartz HL, Surks MI. Specific nuclear triiodothyronine binding sites in rat liver and kidney. J Clin Endocrinol Metab. 1972 Aug;35(2):330-3. [23] Samuels HH, Tsai JS. Thyroid hormone action in cell culture: domonstration of nuclear receptors in intact cells and isolated nuclei. Proc Natl Acad Sci U S A. 1973

[24] Li R, Luciakova K, Zaid A, Betina S, Fridell E, Nelson BD. Thyroid hormone activates transcription from the promoter regions of some human nuclear-encoded genes of the oxidative phosphorylation system. Mol Cell Endocrinol. 1997 Apr 4;128(1-2):69-75. [25] Goglia F, Silvestri E, Lanni A. Thyroid hormones and mitochondria. Biosci Rep. 2002

phosphate potentials in rat liver. Endocrinology. 1992 Jul;131(1):400-7.

fatty acids. Biochim Biophys Acta. 1989 Sep 28;976(2-3):241-5.

different thyroid status. J Biol Chem. 1993 Jul 15;268(20):14850-60.

Biochem. 1992 Jun 15;206(3):775-81.

Biochem J. 1979 Feb 15;178(2):505-7.

Biophys Acta. 1991 Dec 3;1133(1):89-94.

man. J Clin Invest. 1985 Aug;76(2):757-64.

Clin Endocrinol (Oxf). 1980 Nov;13(5):489-506.

Metab. 1999 Apr;84(4):1378-85.

1995;15:263-91.

Dec;70(12):3488-92.

Feb;22(1):17-32.
