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The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoRΔID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T(4) and T(3) concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T(4) and T(3) and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic-pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell-specific TH action that would not be reflected by the serum TSH.

One bout of exercise enhances insulin-stimulated glucose uptake (insulin action), but the effect is blunted by consumption of carbohydrate-containing food after exercise. The independent roles of energy and carbohydrate in mediating post-exercise insulin action have not been systematically evaluated in humans. The purpose of this study was to determine if varying carbohydrate availability, with energy intake held constant, mediates post-exercise insulin action. Ten young (21 +/- 2 y, overweight (body fat 37% +/- 3%) men and women completed 3 conditions in random order: (i) no-exercise (BASE), (ii) exercise with energy balance but carbohydrate deficit (C-DEF), and (iii) exercise with energy and carbohydrate balance (C-BAL). In the exercise conditions, subjects expended 30% of total daily energy expenditure on a cycle ergometer at 70% VO2 peak. Following exercise, subjects consumed a meal that replaced expended energy (~3000 kJ) and was either balanced (intake = expenditure) or deficient (-100 g) in carbohydrate. Twelve hours later, insulin action was measured by continuous infusion of glucose with stable isotope tracer (CIG-SIT). Changes in insulin action were evaluated using a one-way ANOVA with repeated measures. During CIG-SIT, non-oxidative glucose disposal (i.e., glucose storage) was higher in C-DEF than in BASE (27.2 +/- 3.2 vs. 16.9 +/- 3.5 micromol.L-1.kg-1.min-1, p < 0.05). Conversely, glucose oxidation was lower in C-DEF (8.6 +/- 1.3 micromol.L-1.kg-1.min-1) compared with C-BAL (12.2 +/- 1.2 micromol.L-1.kg-1.min-1), and BASE (17.1 +/- 2.2 micromol.L-1.kg-1.min-1), p < 0.05). Fasting fat oxidation was higher in C-DEF than in BASE (109.8 +/- 10.5 vs. 80.7 +/- 9.6 mg.min-1, p < 0.05). In C-DEF, enhanced insulin action was correlated with the magnitude of the carbohydrate deficit (r = 0.82, p < 0.01). Following exercise, re-feeding expended energy, but not carbohydrate, increased fasting fat oxidation, and shifted insulin-mediated glucose disposal toward increased storage and away from oxidation.

Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TR␤) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1 ؊/؊ mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 (Ncor1) allele that cannot interact with TR␤, termed NCoR⌬ID, have low TH levels and normal TSH. We hypothesized that Src-1 T he maintenance of thyroid hormone (TH) levels is essential for development, metabolism, energy expenditure, and thermoregulation. TH levels are sustained by a negative-feedback loop within the hypothalamic-pituitary-thyroid (HPT) axis that operates to keep TH levels, both the predominant form, thyroxine (T 4 ), and the active form, triiodothryonine (T 3 ), within a precise range (1). Thyrotropin-releasing hormone (TRH) from the paraventricular nucleus of the hypothalamus (PVH) stimulates the release of thyroid-stimulating hormone (TSH) from the pituitary. TSH acts on the thyroid to synthesize and release TH, which then signals back to both the PVH and pituitary to suppress TRH and TSH levels, respectively (2). At the molecular level, T 3 mediates its actions through its nuclear receptor isoforms, thyroid hormone receptor alpha (TR␣) and TR␤ (encoded by Thra and Thrb), which function as ligand-dependent transcription factors to either increase or decrease expression of target genes (3-5). Classically, on positively regulated TH targets, the presence of T 3 allows the binding of coactivators, such as the steroid receptor coactivator family (SRC-1, -2, and -3) (6-8). These coactivators then recruit machinery to allow the activation of gene expression (9-12). In the absence of ligand, corepressors, such as nuclear corepressor 1 (NCoR1) or silencing mediator of retinoic acid (SMRT, or NCoR2), bind and recruit complexes to repress transcription (13-18). The processes by which negative TH targets are repressed or transcribed are not well understood, but active T 3 repression does require .In previous reports, our laboratory has demonstrated that NCoR1 also mediates T 3 sensitivity and is critical in maintaining normal TH levels (23-25). NCoR1 binds to TR through two of its three nuclear-receptor-interacting domains, N2 and N3 (26-32). Mice globally expressing a conditional Ncor1 allele lacking N2 and N3, termed NCoR⌬ID, either during embryogenesis or postnatally, have decreased levels of T 4 and T 3 and normal TSH levels (24,25). In addition to altering the set point of the HPT axis, NCoR⌬ID increases the sensitivity of peripheral tissues, such as the liver, to T 3 . This enhanced sensitivity leads to the increased activation of target genes in the presence of similar amounts of T 3 (24). The role of NCoR1 in determining ligand sensitivity in the context of nuclear receptor signaling has been demonstrated by other groups using a mouse model with disrupted interaction between NCoR1 and histone deacetylase 3 (H...