Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance

• Published in: Cell metabolism Vol. 37; no. 4; pp. 936 - 953.e7
• Main Authors: Miro, Caterina, Cicatiello, Annunziata Gaetana, Nappi, Annarita, Sagliocchi, Serena, Acampora, Lucia, Restolfer, Federica, Cuomo, Ornella, de Alteris, Giulia, Pugliese, Gabriella, Torabinejad, Sepehr, Maritato, Rosa, Murolo, Melania, Di Cicco, Emery, Velotti, Nunzio, Capuano, Marianna, La Civita, Evelina, Terracciano, Daniela, Ciampaglia, Roberto, Stornaiuolo, Mariano, Musella, Mario, Aprea, Giovanni, Pignataro, Giuseppe, Savastano, Silvia, Dentice, Monica
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2025
• Subjects: alpha-MSH - metabolism; Animals; Cyclic AMP - metabolism; deiodinases; energy homeostasis; Energy Metabolism - drug effects; glucose uptake; Humans; Iodide Peroxidase - genetics; Iodide Peroxidase - metabolism; Iodothyronine Deiodinase Type II; leptin; Leptin - administration & dosage; Leptin - metabolism; Leptin - pharmacology; Male; melanocortin; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; obesity; Obesity - metabolism; Signal Transduction; skeletal muscle; STAT3 Transcription Factor - metabolism; thyroid hormone; Thyroid Hormones - metabolism; thyroid hormone; glucose uptake; deiodinases; skeletal muscle; leptin; energy homeostasis; obesity; melanocortin
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2025.01.025

Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin’s peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores. [Display omitted] •D2 is upregulated in the muscles of overweight subjects while suppressed in obesity•Leptin induces the expression of D2 in skeletal muscle via the leptin receptor•The mechanism by which leptin induces D2 is STAT3 and α-MSH dependent•An intact TH signaling is required for the leptin-mediated peripheral metabolic effects In this study, Miro et al. report that the adipocyte-derived leptin is an upstream activator of thyroid hormone (TH) in skeletal muscle, increasing metabolic rate in conditions of excess weight gain. Notably, this mechanism is lost in obesity due to the leptin resistance, with a consequent impact on whole-body energetics.