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Rial-Pensado, E.* ; Canaple, L.* ; Guyot, R.* ; Clemmensen, C. ; Wiersema, J.* ; Wu, S.* ; Richard, S.* ; Boelen, A.* ; Müller, T.D. ; López, M.* ; Flamant, F.* ; Gauthier, K.*

Neuronal blockade of thyroid hormone signaling increases sensitivity to diet-induced obesity in adult male mice.

Endocrinology 164:12 (2023)

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Thyroid hormone increases energy expenditure. Its action is mediated by TR, nuclear receptors present in peripheral tissues and in the central nervous system, particularly in hypothalamic neurons. Here, we address the importance of thyroid hormone signaling in neurons, in general for the regulation of energy expenditure. We generated mice devoid of functional TR in neurons using the Cre/LoxP system. In hypothalamus, which is the center for metabolic regulation, mutations were present in 20 to 42% of the neurons. Phenotyping was performed under physiological conditions that trigger adaptive thermogenesis: cold and high fat diet (HFD) feeding. Mutant mice displayed impaired thermogenic potential in brown and inguinal white adipose tissues and were more prone to diet-induced obesity. They showed a decreased energy expenditure on chow diet, and gain more weight on HFD. This higher sensitivity to obesity disappeared at thermoneutrality. Concomitantly, the AMPK pathway was activated in the ventromedial Hypothalamus (VMH) of the mutants as compared to the controls. In agreement sympathetic nervous system (SNS) output, visualized by tyrosine hydroxylase expression was lower in the brown adipose tissue (BAT) of the mutants. In contrast, absence of TR signaling in the mutants did not affect their ability to respond to cold exposure. This study provides the first genetic evidence that thyroid hormone signaling exerts a significant influence in neurons to stimulate energy expenditure in some physiological context of adaptive thermogenesis. TR function in neurons to limit weight gain in response to HFD and this effect is associated with a potentiation of SNS output.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Thyroid Hormone ; Adaptive Thermogenesis ; Brown Adipose Tissue ; Cold Exposure ; Diet Induced Obesity ; Neurons ; Sympathetic Nervous System (sns); Type-2 Iodothyronine Deiodinase; Brown Adipose-tissue; Ventromedial Nucleus; Energy-expenditure; Hypothalamic Ampk; Thermogenesis; Mouse; Metabolism; Receptors; Mutation

ISSN (print) / ISBN 0013-7227

e-ISSN 1945-7170

Journal Endocrinology

Quellenangaben Volume: 164, Issue: 4, Article Number: 12

Publisher Endocrine Society

Publishing Place Chevy Chase, Md.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)