Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Miguel López (Corresponding Author), Luis Varela, María J. Vázquez, Sergio Rodríguez-Cuenca, Carmen R. González, Vidya Velagapudi, Donald A. Morgan, Erik Schoenmakers, Kristofor Agassandian, Ricardo Lage, Pablo Blanco Martínez de Morentin, Sulay Tovar, Rubén Nogueiras, David Carling, Christopher Lelliott, Rosalía Gallego, Matej Orešič, Krishna Chatterjee, Asish K. Saha, Kamal Rahmouni & 2 others Carlos Diéguez, Antonio Vidal-Puig

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.
Original languageEnglish
Pages (from-to)1001-1008
JournalNature Medicine
Volume16
DOIs
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

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AMP-Activated Protein Kinases
Neurology
Energy balance
Metabolism
Hypothalamus
Brown Adipose Tissue
Thyroid Gland
Hyperthyroidism
Fatty Acids
Weight Loss
Sympathetic Nervous System
Tissue
Thyroid Hormones
Central Nervous System
Thyroid Hormone Receptors
Triiodothyronine
Lipid Metabolism
Rats
Homeostasis
Up-Regulation

Cite this

López, M., Varela, L., Vázquez, M. J., Rodríguez-Cuenca, S., González, C. R., Velagapudi, V., ... Vidal-Puig, A. (2010). Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nature Medicine, 16, 1001-1008. https://doi.org/10.1038/nm.2207
López, Miguel ; Varela, Luis ; Vázquez, María J. ; Rodríguez-Cuenca, Sergio ; González, Carmen R. ; Velagapudi, Vidya ; Morgan, Donald A. ; Schoenmakers, Erik ; Agassandian, Kristofor ; Lage, Ricardo ; Martínez de Morentin, Pablo Blanco ; Tovar, Sulay ; Nogueiras, Rubén ; Carling, David ; Lelliott, Christopher ; Gallego, Rosalía ; Orešič, Matej ; Chatterjee, Krishna ; Saha, Asish K. ; Rahmouni, Kamal ; Diéguez, Carlos ; Vidal-Puig, Antonio. / Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. In: Nature Medicine. 2010 ; Vol. 16. pp. 1001-1008.
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abstract = "Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.",
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López, M, Varela, L, Vázquez, MJ, Rodríguez-Cuenca, S, González, CR, Velagapudi, V, Morgan, DA, Schoenmakers, E, Agassandian, K, Lage, R, Martínez de Morentin, PB, Tovar, S, Nogueiras, R, Carling, D, Lelliott, C, Gallego, R, Orešič, M, Chatterjee, K, Saha, AK, Rahmouni, K, Diéguez, C & Vidal-Puig, A 2010, 'Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance', Nature Medicine, vol. 16, pp. 1001-1008. https://doi.org/10.1038/nm.2207

Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. / López, Miguel (Corresponding Author); Varela, Luis; Vázquez, María J.; Rodríguez-Cuenca, Sergio; González, Carmen R.; Velagapudi, Vidya; Morgan, Donald A.; Schoenmakers, Erik; Agassandian, Kristofor; Lage, Ricardo; Martínez de Morentin, Pablo Blanco; Tovar, Sulay; Nogueiras, Rubén; Carling, David; Lelliott, Christopher; Gallego, Rosalía; Orešič, Matej; Chatterjee, Krishna; Saha, Asish K.; Rahmouni, Kamal; Diéguez, Carlos; Vidal-Puig, Antonio (Corresponding Author).

In: Nature Medicine, Vol. 16, 2010, p. 1001-1008.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Velagapudi, Vidya

AU - Morgan, Donald A.

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AU - Martínez de Morentin, Pablo Blanco

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AU - Rahmouni, Kamal

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AB - Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

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López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi V et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nature Medicine. 2010;16:1001-1008. https://doi.org/10.1038/nm.2207