Thyroid hormone has profound effects on metabolic homeostasis, regulating both 
lipogenesis and lipolysis, primarily by modulating adrenergic activity. We 
generated mice with a point mutation in the thyroid hormone receptor alpha 
(TRalpha) gene producing a dominant-negative TRalpha mutant receptor with a 
proline to histidine substitution (P398H). The heterozygous P398H mutant mice 
had a 3.4-fold (p < 0.02) increase in serum thyrotropin (TSH) levels. Serum 
triiodothyronine (T3) and thyroxine (T4) concentrations were slightly elevated 
compared with wild-type mice. The P398H mice had a 4.4-fold increase in body fat 
(as a fraction of total body weight) (p < 0.001) and a 5-fold increase in serum 
leptin levels (p < 0.005) compared with wild-type mice. A 3-fold increase in 
serum fasting insulin levels (p < 0.002) and a 55% increase in fasting glucose 
levels (p < 0.01) were observed in P398H compared with wild-type mice. There was 
a marked reduction in norepinephrine-induced lipolysis, as reflected in reduced 
glycerol release from white adipose tissue isolated from P398H mice. Heart rate 
and cold-induced adaptive thermogenesis, mediated by thyroid 
hormone-catecholamine interaction, were also reduced in P398H mice. In 
conclusion, the TRalpha P398H mutation is associated with visceral adiposity and 
insulin resistance primarily due to a marked reduction in 
catecholamine-stimulated lipolysis. The observed phenotype in the TRalpha P398H 
mouse is likely due to interference with TRalpha action as well as influence on 
other metabolic signaling pathways. The physiologic significance of these 
findings will ultimately depend on understanding the full range of actions of 
this mutation.