A TRβ-selective agonist confers resistance to diet-induced obesity

Abstract

Thyroid hormone receptor b (TRb 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 TRb 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 TRb-selective agonist, GC-24 only partially improves metabolic control probably as a result of accelerating the resting metabolic rate.

Role of thyroid hormone in skeletal muscle physiology

“…THRs also act as transcription factors independent of the ligand (Ortiga-Carvalho et al 2015). THRA is the main isoform present in SM (Miyabara et al 2005, Amorim et al 2009, Dentice et al 2010, Milanesi et al 2016.…”

Human Brown Adipose Tissue: What We Have Learned So Far

“…However, adverse symptoms such as tachycardia are mainly related to the activation of THRa. Selective targeting of THRb, on the other hand, conferred resistance to diet-induced obesity by increased BAT activity and was well tolerated in rats (87,88). Additionally, in mice, bile acids have been shown to increase DIO2 expression by binding to TGR5, a G s -protein-coupled transmembrane receptor, and thus to increase the local availability of triiodothyronine and energy expenditure (89,90).…”

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

“…In rats, the drug reduces body fat accumulation, prevents liver steatosis, improves insulin sensitivity, and normalizes hypertriglyceridemia (183). These favorable actions can be obtained without significant changes in food intake or untoward cardiac effects.…”