Thyroid Analogs and Obesity

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 produce the opposite effect. Of the four T3 receptors, only the isoform TR?1 has been shown to be essential for thermogenesis. In contrast to expectations though, thermogenesis was increased in mice null for TR?1 (Pelletier, Gauthier, Sideleva, Samarut, and Silva, 2008). The mechanism that produced this result seems to involve a block on sympathetic activation of thermogenesis in adipose tissue, which in turn caused an alternative pathway to activate thermogenesis when the mice were placed in a cool room. These findings are supported by a previous study showing a dominant-negative form of TR?1 blocked sympathetic activation and increased basal metabolic levels (Sjogren et al., 2007). The mutant mice from both studies had a lean body phenotype and were resistant to diet-induced obesity. In a recent human study, higher levels of TR?1mRNA were found to be present in subcutaneous vs. visceral adipose tissue, and this difference increased when comparing obese women to lean controls (Ortega, Moreno-Navarrete, Ribas, Esteve, Rodriquez-Hermosa, Ruiz et al. 2009). The authors of this study interpreted their findings as suggesting the elevated levels of TR?1mRNA in subcutaneous adipose tissue in obese women facilitates its expansion.