Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia.
Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor beta (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 alpha sensitivity to elevated thyroid hormone levels.
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
Catherine S
CS
Mitchell
David B
DB
Savage
Sylvie
S
Dufour
Nadia
N
Schoenmakers
Peter
P
Murgatroyd
Douglas
D
Befroy
David
D
Halsall
Samantha
S
Northcott
Philippa
P
Raymond-Barker
Suzanne
S
Curran
Elana
E
Henning
Julia
J
Keogh
Penny
P
Owen
John
J
Lazarus
Douglas L
DL
Rothman
I Sadaf
IS
Farooqi
Gerald I
GI
Shulman
Krishna
K
Chatterjee
Kitt Falk
KF
Petersen
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000328:Adult; D002648:Child; D002952:Citric Acid Cycle; D004435:Eating; D004734:Energy Metabolism; D006801:Humans; D006963:Hyperphagia / Q000209:etiology* / Q000378:metabolism; D007333:Insulin Resistance; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D018382:Thyroid Hormone Resistance Syndrome / Q000378:metabolism*
D037042:Thyroid Hormone Receptors beta; D000255:Adenosine Triphosphate