Triiodothyronine and leptin repletion in humans similarly reverse weight-loss-induced changes in skeletal muscle

Sub-jects maintaining a ≥10% dietary weight loss exhibit decreased circulating concentrations of bioactive thyroid hormones and increased skeletal muscle work efficiency largely due to increased expression of more-efficient myosin heavy chain (MHC) isoforms (MHC I) and significantly mediated by the adipocyte-derived hormone leptin. The primary purpose of this study was to examine the effects of triiodothyronine (T₃) repletion on energy homeostasis and skeletal muscle physiology in weight-reduced subjects and to compare these results with the effects of leptin repletion. Nine healthy inpatients with obesity were studied at usual weight (Wt_initial) and following a 10% dietary weight loss while receiving 5 wk of a placebo (Wt_-10%placebo) or T₃ (Wt_-10%T3) in a single-blind crossover design. Primary outcome variables were skeletal muscle work efficiency and vastus lateralis muscle mRNA expression. These results were compared with the effects of leptin repletion in a population of 22 subjects, some of whom participated in a previous study. At Wt_-10%placebo, skeletal muscle work efficiency and relative expression of the more-efficient/less-efficient MHC I/MHC II isoforms were significantly increased and the ratio of the less-efficient to the more-efficient sarco(endo)plasmic reticulum Ca²⁺-ATPase isoforms (SERCA1/ SERCA2) was significantly decreased. These changes were largely reversed by T₃ repletion to a degree similar to the changes that occurred with leptin repletion. These data support the hypothesis that the effects of leptin on energy expenditure in weight-reduced individuals are largely mediated by T₃ and suggest that further study of the possible role of thyroid hormone repletion as adjunctive therapy to help sustain weight loss is needed.