TY - JOUR

T1 - Neuronal Blockade of Thyroid Hormone Signaling Increases Sensitivity to Diet-Induced Obesity in Adult Male Mice

AU - Rial-Pensado, Eva

AU - Canaple, Laurence

AU - Guyot, Romain

AU - Clemmensen, Christoffer

AU - Wiersema, Joëlle

AU - Wu, Shijia

AU - Richard, Sabine

AU - Boelen, Anita

AU - Müller, Timo D

AU - López, Miguel

AU - Flamant, Frédéric

AU - Gauthier, Karine

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2023

Y1 - 2023

N2 - 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 gained more weight on HFD. This higher sensitivity to obesity disappeared at thermoneutrality. Concomitantly, the AMPK pathway was activated in the ventromedial hypothalamus of the mutants as compared with the controls. In agreement, sympathetic nervous system (SNS) output, visualized by tyrosine hydroxylase expression, was lower in the brown adipose tissue 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.

AB - 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 gained more weight on HFD. This higher sensitivity to obesity disappeared at thermoneutrality. Concomitantly, the AMPK pathway was activated in the ventromedial hypothalamus of the mutants as compared with the controls. In agreement, sympathetic nervous system (SNS) output, visualized by tyrosine hydroxylase expression, was lower in the brown adipose tissue 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.

KW - Male

KW - Mice

KW - Animals

KW - Obesity/genetics

KW - Thyroid Hormones/metabolism

KW - Diet, High-Fat/adverse effects

KW - Adipose Tissue, Brown/metabolism

KW - Neurons/metabolism

KW - Thermogenesis/physiology

KW - Energy Metabolism/genetics

U2 - 10.1210/endocr/bqad034

DO - 10.1210/endocr/bqad034

M3 - Journal article

C2 - 36801988

VL - 164

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0013-7227

IS - 4

ER -