Thyroid Analogs and Obesity Term Paper

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Thyroid Hormone and Obesity

Obesity Treatment: The Efficacy and Safety of Thyroid Hormone and Derivatives

Weight loss programs have traditionally focused on calorie intake reduction in combination with exercise, but new research suggests that it may be possible to simply accelerate metabolic rates using pharmaceutical interventions. The current drugs approved for treating obesity function by suppressing hunger or limiting nutritional absorption (reviewed by Tseng, Cypess, and Kahn, 2010). Unfortunately, the body is designed adapt to caloric availability by lowing metabolic rates during famine and to store calories as fat to guard against starvation. Drugs that suppress hunger or limit absorption activate these pathways, making long-term weight loss more difficult. The drugs that act on the satiety centers in the brain can also produce debilitating psychotropic side effects. The current state of effective pharmaceutical intervention on behalf of obese patients is therefore lacking approved drugs that increase calorie expenditure safely over the long-term.

For decades thyroid hormone (TH) has been recognized as an important regulator of metabolism, and in particular, thermogenesis (reviewed by Herwig, Ross, Nilaweera, Morgan, and Barrett, 2008). Treating obese patients with TH did increase metabolic activity and weight loss, but there were several serious side effects, including heart arrhythmia, bone loss, and muscle catabolism (reviewed by Tseng, Cypess, and Kahn, 2010). The seriousness of these side effects, in combination with the promise of an eventual effective treatment, led to the development and testing of TH mimetics with the hope that chemically modifying TH could provide the benefits of TH supplementation without the serious side effects. After decades of such trials, none have been approved for treating obesity because of similarly serious side effects (reviewed in Baxter and Webb, 2009). In the meantime scientific investigations have continued to investigate the TH pathway, leading to a better understanding of the mechanisms involved. For this reason, efforts to develop and test 'smarter' TH mimetics are underway.

Another approach that has received some attention is the manipulation or modification of TH receptors. Years of research have shown that the thyroid hormone triiodothyronine (T3) is important for maintaining proper body weight and regulating thermogenesis (reviewed by Sjogren, Alkemade, Mittag, Nordstrom, Katz, Rozell et al., 2007); low levels of T3 lead to weight gain and cold intolerance, while high levels…

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References

Baxter, John D. And Webb, Paul. (2009). Thyroid hormone mimetics: potential applications in atherosclerosis, obesity, and type 2 diabetes. Nature Reviews in Drug Discovery, 8, 308-320.

Herwig, Annika, Ross, Alexander W., Nilaweera, Kanishka N., Morgan, Peter J., and Barrett, Perry. (2008). Hypothalamic TH in energy balance regulation. Onkologie, 31, 71-79.

Ortega, Francisco J., Moreno-Navarrete, Jose M., Ribas, Vincent, Esteve, Eduardo, Rodriquez-Hermosa, Jose I., Ruiz, Bartomeu et al. (2009). Subcutaneous fat shows higher thyroid hormone receptor-?1 gene expression than omental fat. Obesity, 17, 2134-2141.

Pelletier, Paula, Gauthier, Karine, Sideleva, Olga, Samarut, Jacques, and Silva, J. Enrique. (2008). Mice lacking the thyroid hormone receptor-? gene spend more energy in thermogenesis, burn more fat, and are less sensitive to high-fat diet-induced obesity. Endocrinology, 149, 6471-6486.

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