Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia
Catherine S. Mitchell, … , Krishna Chatterjee, Kitt Falk Petersen
Catherine S. Mitchell, … , Krishna Chatterjee, Kitt Falk Petersen
Published March 8, 2010
Citation Information: J Clin Invest. 2010;120(4):1345-1354. https://doi.org/10.1172/JCI38793.
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Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia

Abstract

Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor β (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor α sensitivity to elevated thyroid hormone levels.

Authors

Catherine S. Mitchell, David B. Savage, Sylvie Dufour, Nadia Schoenmakers, Peter Murgatroyd, Douglas Befroy, David Halsall, Samantha Northcott, Philippa Raymond-Barker, Suzanne Curran, Elana Henning, Julia Keogh, Penny Owen, John Lazarus, Douglas L. Rothman, I. Sadaf Farooqi, Gerald I. Shulman, Krishna Chatterjee, Kitt Falk Petersen

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Figure 1

Energy expenditure in patients with RTH.

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Energy expenditure in patients with RTH. (A) REE expressed per unit LBM ...
(A) REE expressed per unit LBM in control (gray circles, n = 45), adult RTH (black circles, n = 52), and thyrotoxic (white circles, n = 11) subjects. (B) Relationship between REE and LBM in control, RTH, or thyrotoxic subjects. (C and D) Relationship between REE/LBM and fT4 (C) or fT3 levels (D) in control (n = 45), RTH (n = 46), and thyrotoxic (n = 10) subjects, excluding subjects on exogenous levothyroxine or triiodothyronine (RTH, n = 6; thyrotoxic, n = 1). (E) Relationship between mean sleeping heart rate and REE/LBM in RTH (black circles, n = 42) and thyrotoxic subjects (white circles, n = 11). Data was not available for 10 RTH subjects. (F) Correlation of the mean T3 binding affinity of the type 1 mutant TRβs with mean fT4 level in RTH subjects, excluding subjects on exogenous levothyroxine. Type 1 mutants (black circles, n = 7) follow the regression line describing this correlation; type 2 mutants (white circles, n = 3) have mutations significantly deviating from this relationship. Each data point represents mean ± SD for all subjects with that particular THRB mutation. Ka indicates the binding affinity constant of thyroid receptor (WT or mutant) for T3. (G) Correlation of mean REE/LBM with T3 binding affinity of type 1 (black circles, n = 6) and type 2 mutant TRβs (white circles, n = 3) in RTH subjects. Each data point represents mean ± SD for all subjects with that particular THRB mutation. (H) BMR expressed per unit LBM in control (gray circles, n = 22) and RTH subjects (black circles, n = 13), matched for age, gender, weight and BMI. Diagonal lines indicate the regression lines (B–G). Horizontal lines indicate the mean (A and H). r, Pearson product moment correlation coefficient.