A TRbeta-selective agonist confers resistance to diet-induced obesity.

Thyroid hormone receptor beta (TRbeta also listed as THRB on the MGI Database)-selective agonists activate brown adipose tissue (BAT) thermogenesis, while only minimally affecting cardiac activity or lean body mass. Here, we tested the hypothesis that daily administration of the TRbeta agonist GC-24 prevents the metabolic alterations associated with a hypercaloric diet. Rats were placed on a high-fat diet and after a month exhibited increased body weight (BW) and adiposity, fasting hyperglycemia and glucose intolerance, increased plasma levels of triglycerides, cholesterol, nonesterified fatty acids and interleukin-6. While GC-24 administration to these animals did not affect food ingestion or modified the progression of BW gain, it did increase energy expenditure, eliminating the increase in adiposity without causing cardiac hypertrophy. Fasting hyperglycemia remained unchanged, but treatment with GC-24 improved glucose tolerance by increasing insulin sensitivity, and also normalized plasma triglyceride levels. Plasma cholesterol levels were only partially normalized and liver cholesterol content remained high in the GC-24-treated animals. Gene expression in liver, skeletal muscle, and white adipose tissue was only minimally affected by treatment with GC-24, with the main target being BAT. In conclusion, during high-fat feeding treatment with the TRbeta-selective agonist, GC-24 only partially improves metabolic control probably as a result of accelerating the resting metabolic rate.

Mice with impaired extrathyroidal thyroxine to 3,5,3'-triiodothyronine conversion maintain normal serum 3,5,3'-triiodothyronine concentrations.

For T(3) to mediate its biological effects, the prohormone T(4) must be activated by removal of an outer-ring iodine by the type 1 or 2 deiodinases (D1 and D2) with approximately 60% of the daily T(3) production in rodents being produced extrathyroidally through this pathway. To further define the role of these enzymes in thyroid hormone homeostasis, we backcrossed the targeted disruption of the Dio2 gene into C3H/HeJ (C3H) mice with genetically low D1 expression to create the C3H-D2KO mouse. Remarkably, these mice maintain euthyroid serum T(3) levels with normal growth and no decrease in expression of hepatic T(3)-responsive genes. However, serum T(4) is increased 1.2-fold relative to the already elevated C3H levels, and serum TSH is increased 1.4-fold. Despite these increases, thyroidal (125)I uptake indicates no difference in thyroidal activity between C3H-D2KO and C3H mice. Although C3H-D2KO hepatic and renal D1 activities were well below those observed in wild-type mice (approximately 0.1-fold for both), they were 8-fold and 2-fold higher, respectively, relative to C3H mice. Thyroidal D1 and cerebral cortical type 3 deiodinase activity were unchanged between C3H-D2KO and C3H mice. In conclusion, C3H-D2KO mice have notably elevated serum T(4) levels, and this, in conjunction with residual D1 activity, is likely an important role in the maintenance of euthyroid serum T(3) concentrations.