Adipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects

• Published in: Nature communications Vol. 13; no. 1; p. 7838
• Main Authors: Chen, Kang, Cheong, Lai Yee, Gao, Yuan, Zhang, Yaming, Feng, Tianshi, Wang, Qin, Jin, Leigang, Honoré, Eric, Lam, Karen S. L., Wang, Weiping, Hui, Xiaoyan, Xu, Aimin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 14/19; 38/77; 64/60; 692/163/2743; 692/698/690/2816; 692/700/565/1436; 82/51; Adipose tissue; Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; Animals; Apolipoprotein E; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; Body fat; Body weight loss; Complications; Drug-Related Side Effects and Adverse Reactions; Energy Metabolism; Fatty liver; Feedback; Glucose tolerance; Humanities and Social Sciences; Hypercholesterolemia; Innervation; Insulin; Insulin resistance; Intolerance; Liposomes; Mice; Mice, Inbred C57BL; multidisciplinary; Obesity; Obesity - metabolism; Science; Science (multidisciplinary); Side effects; Therapy; Thermogenesis; Thyroid; Thyroid gland; Thyroid hormones; Thyroid Hormones - metabolism; Triiodothyronine; Triiodothyronine - metabolism; Weight control; Weight loss; Weight reduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35470-4

Thyroid hormone (TH) is a thermogenic activator with anti-obesity potential. However, systemic TH administration has no obvious clinical benefits on weight reduction. Herein we selectively delivered triiodothyronine (T3) to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3). Systemic T3 administration failed to promote thermogenesis in brown and white adipose tissues (WAT) due to a feedback suppression of sympathetic innervation. PLT3 therapy effectively obviated this feedback suppression on adrenergic inputs, and potently induced browning and thermogenesis of WAT, leading to alleviation of obesity, glucose intolerance, insulin resistance, and fatty liver in obese mice. Furthermore, PLT3 was much more effective than systemic T3 therapy in reducing hypercholesterolemia and atherosclerosis in apoE-deficient mice. These findings uncover WAT as a viable target mediating the therapeutic benefits of TH and provide a safe and efficient therapeutic strategy for obesity and its complications by delivering TH to adipose tissue. Although thyroid hormone (TH) has anti-obesity potential, systemic administration of TH causes severe adverse effects without obvious weight loss. Here, the authors show that adipose tissue-targeted delivery of TH with liposomes is a safe and efficient strategy to treat obesity and its related complications in mice.