Effects of in vivo 3-iodothyronamine administration on gene expression in adipose tissue.

Thyroid hormones (THs) control the adipose tissue development and metabolism. They regulate both adipocyte proliferation and differentiation and, as they cause weight loss by increasing the metabolic rate, may be useful for obesity treatment. However, due to their cardiotoxic effects, like tachycardia and arrhythmia, their use is limited to hypothyroid obese patients. Some TH metabolites have been recently shown to possess the same beneficial metabolic effects as THs without the same negative effects. A biogenic amine named 3-Iodothyronamine (T1AM), i.e., is an endogenous compound derived by thyroxine (T4) deiodination and decarboxylation that affects carbohydrate and lipid metabolism without undesirable side effects. T1AM exhibits cardiac effects opposite to those associated with thyroid hormones, like bradycardia in mice, and in isolated working rat heart, it produces a rapid, reversible, dose-dependent decrease in cardiac output, aortic pressure and coronary flow. These findings suggest that T1AM produces a negative inotropic and chronotropic effect. Intraperitoneal injections of T1AM also induce reduction of RQ from 0.9 to 0.7, both in mice and Djungarian hamsters. This indicates that carbohydrate utilisation is reduced in response to T1AM and energy requirements are covered by lipid utilisation. Interestingly, the complete RQ shift is reached 4.5 h after the T1AM injection and persists at least for 24 hours. Ketone bodies in the urine and the significant loss of body fat mass confirm that lipids are predominantly used to cover the energy requirements in response to T1AM administration. The molecular mechanisms by which T1AM favours lipid than glucose catabolism are not known, but changes in gene expression can be hypothesized, given the delayed and long lasting phenotypical effects of T1AM. To verify this hypothesis we analyzed by microarrays the gene expression profiles in subcutaneous adipose tissues of eight rats chronically treated with T1AM as compared with eight untreated rats. Many genes linked to lipid metabolism, adipogenesis and angiogenesis appeared affected by chronic administration of T1AM, thus explaining, at least in part, the T1AM phenotypic effects observed in rodents. Furthermore, T1AM influenced the expression of several genes relating to lipoprotein metabolism that provide new insights on T1AM mechanism of action, like, i.e., the regulation of cholesterol homeostasis